Fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient

ABSTRACT

Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each symbol has the meaning as defined in the specification.). 
     
       
         
         
             
             
         
       
     
     Because of inhibiting poly(ADP-ribose)polymerase, the compounds represented by formula (I) are useful as preventives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebrosclerosis, arthritis, etc.), neurodegenerative diseases (extrapyramidal disorder, Alzheimer&#39;s disease, muscular dystrophy, lumbar spinal canal stenosis, etc.), diabetes, shock, head trauma, renal failure, hyperalgesia, etc. Moreover, these compounds are useful as agents against retroviruses (HIV etc.), sensitizers in treating cancer and immunosuppressants.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Divisional of U.S. application Ser. No. 10/505,012 filed Aug.18, 2004, which is a 371 of PCT Application No. PCT/JP03/01694, Feb. 18,2003, which claims priority from Japanese Application No. 2002-42259filed on Feb. 19, 2002 and 2002-199673 filed on Jul. 9, 2002. Theabove-noted applications are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to fused pyridazine derivative compounds.

More particularly, the present invention relates to

(1) pyridazine derivative compounds represented by formula (I)

(wherein all symbols have the same meanings as described below), orpharmaceutically acceptable salts thereof,(2) a process for preparing thereof, and(3) an agent comprising the same as an active ingredient.

BACKGROUND ART

Poly(ADP-ribose)polymerase (abbreviated as PARP hereinafter), which is anuclear enzyme activated by DNA strand breaks, plays a role in thetransfer reaction of ADP-ribose moiety from nicotinamide adeninedinucleotide (abbreviated as NAD⁺ hereinafter) to various proteins suchas histones, DNA-polymerases and DNA-topoisomerases, etc.

DNA strand breaks caused by Peroxynitrite (ONOO⁻) and oxygen radicalslead to overactivation of PARP (PARP is activated up to 100 times whenZn finger domain of PARP binds to DNA with nicks.). It is thought thatoveractivation of PARP causes depletion of NAD⁺, which is essential forelectron transport system, and consequently depletion of ATP, leading toenergy failure, ultimately resulting in cell death. (The suicidehypothesis of PARP activation: Free Radic. Biol Med., 21, 855 (1996);TIPS., 19, 287 (1998)). Therefore, it is considered that PARP inhibitoris useful as inhibitor of cell death.

Since caspase-3, which is one of interleukin-1β-converting enzymefamily, specifically cleaves PARP as the substrate (Cell., 81, 801(1995)), it is suggested PARP is associated with apoptosis.

It is reported that 3-aminobenzamide and nicotinamide generally known asinhibitors of PARP are useful for inhibition of cell death andimprovement of diseases on various models of ischemic diseases(cerebral, myocardial, intestinal, skeletal muscular or retinal ischemiaetc.), inflammatory diseases (arthritis, inflammatory bowel disease ormultiple sclerosis etc.), diabetes, shock, extrapyramidal disease(TIPS., 19, 287 (1998); Eur J. Pharmacol., 350, 1 (1998)) andhyperalgesia (Pain, 72, 355 (1997)) in vitro, in vivo and in PARPknockout mouse. And it is reported that PARP inhibitor is useful as anantiretroviral drug such as an anti HIV drug (Biochem. Biophys. Res.Commum., 180, 504 (1991)), a sensitizer of anticancer therapy (Radiat.Res., 126, 367 (1991); Br. J. Cancer., 72, 849 (1995)) or animmunosuppressant (Int. J. Immunopharmac., 17, 265 (1995)).

PARP inhibitor is useful for prevention and/or treatment of variousdiseases, for example, ischemic diseases (cerebral infarction,myocardial infarction, reperfusion injury or postoperative injury etc.),inflammatory diseases (inflammatory bowel disease, multiple sclerosis,arthritis or lung injury etc.), neurodegenerative disorders(extrapyramidal disease, Parkinson's disease, Alzheimer's disease,muscular dystrophy or lumbar spinal canal stenosis etc.), glaucoma,diabetes, diabetic complication, shock, head trauma, spinal cord injury,renal failure, hyperalgesia or blood flow obstruction etc. And it isuseful as an antiretroviral drug such as an anti HIV drug, a sensitizerof anticancer therapy or an immunosuppressant.

As PARP inhibitor, for example, in the specification of WO00/44726, itis described that 2H-phthalazin-1-one derivatives represented by formula(A)

(wherein R^(1A) is(i) C1-4 alkyl substituted by hydroxy or amino, or

(ii) -A^(1A)-A^(2A)-A^(3A),

in which A^(1A) is —NR^(3A)C(O)— etc. wherein R^(3A) is hydrogen or C1-4alkyl etc., A^(2A) is C1-8 alkylene etc., A^(3A) is (i) hydrogen, (ii)—NR^(17A)R^(18A) or (iii) Cyc^(2A) etc. wherein R^(17A) is (i) hydrogen,(ii) C1-8 alkyl etc., and R^(18A) is (i) hydrogen or (ii) C1-8 alkyletc., Cyc^(2A) is 3-10 membered mono- or bi-heterocyclic ring containing1-4 of nitrogen atoms, 1-2 of oxygen atoms and/or one sulfur atom,R^(2A) is hydrogen or halogen etc. Necessary parts were extracted fromthe description of groups.) have PARP inhibitory activity.

In the specification of DE3302021, it is described that compoundsrepresented by formula (B)

(wherein R^(1B) is hydrogen or C1-3 alkyl, R^(2B) is hydrogen, R^(1B)and R^(2B), taken together, are C1-4 alkylene, R^(3B) is hydrogen ormethyl, nB is 0-3, R^(4B) is 1-pyrrolyl. Necessary parts were extractedfrom the description of groups.) have inhibitory activity of plateletaggregation.

In the specification of WO98/31674, it is described that compoundsrepresented by formula (C)

(wherein R^(1C) is C1-4 alkoxy etc., R^(2C) is C1-8 alkoxy etc., R^(3C)and R^(4C) is hydrogen or R^(3C) and R^(4C), taken together, are bond,R^(5C) is hydrogen etc. Necessary parts were extracted from thedescription of groups.) have phosphodiesterase inhibitory activity.

In Journal of Medicinal Chemistry., 44(16), 2511-2522 and 2523-2535(2001), it is described that4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one(CAS Registry No. 244077-36-9) and4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CASRegistry No. 358368-98-6) have phosphodiesterase inhibitory activity.

In Tetrahedron., 39(20), 3419-27 (1983),4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (CASRegistry No. 89311-30-8) is described as synthetic intermediate.

In Synthesis., 240-242 (1995),4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS Registry No.154810-22-7), 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one(CAS Registry No. 154810-23-8),4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS RegistryNo. 154810-24-9),4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS RegistryNo. 154810-25-0), and4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CAS RegistryNo. 154810-26-1) are described as synthetic intermediate.

In Bioorganic and Medicinal Chemistry., 6, 349-454 (1998),7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one(CAS Registry No. 206126-90-1) and4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one (CASRegistry No. 206126-96-7) are described as synthetic intermediate.

In Journal of Medicinal Chemistry., 43(12), 2310-2323 (2000),4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CASRegistry No. 212142-89-7) is described as synthetic intermediate.

In the specification of FR2647676,4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CASRegistry No. 134972-12-6) and4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one (CASRegistry No. 134973-24-3) are described as synthetic intermediate.

DISCLOSURE OF THE INVENTION

In order to find a compound having poly(ADP-ribose)polymerase activity,the present inventors have conducted intensive studies and found, as aresult, that the objects can be accomplished by the pyridazinederivative represented by formula (I), and thus the present inventionhas been accomplished.

The present invention relates to

(1) a fused pyridazine derivative compound represented by formula (I)

wherein R¹ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5)halogen atom, (6) nitro, (7) NR²R³, (8) C2-8 acyl, (9) C1-8 alkoxysubstituted by phenyl or (10) C2-8 acyl substituted by NR²R³,

R² and R³ are each independently

(1) a hydrogen atom or (2) C1-8 alkyl,

X and Y are each independently

(1) C, (2) CH or (3) N,

is

(1) a single bond or (2) a double bond,

(1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2)partially or fully saturated 3-10 membered mono-hetero aryl containing 1to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,

A is (1) A¹, (2) A², (3) A³, (4) A⁴ or (5) A⁵,

A¹ is

A² is -E¹-E²-E³-E⁴,

A³ is

A⁴ is

A⁵ is

D¹ is

(1) —NR⁶C(O)—, (2) —NR⁶C(S)—, (3) —NR⁶SO₂—, (4) —CH₂—NR⁶—, (5) —CH₂—O—,(6) —OC(O)—, (7) —CH₂—NR⁶C(O)—, (8) —NR⁶C(O)NR⁷—, (9) —NR⁶C(O)O—, (10)—NR⁶C(S)NR⁷—, (11) —NR⁶— or (12) —NR⁶C(═NR⁷)—,

R⁶ and R⁷ are each independently

(1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkylsubstituted by phenyl,

D2 is

(1) C1-8 alkylene, (2) C2-8 alkenylene, (3) Cyc2, (4) —(C1-4alkylene)-O—(C1-4 alkylene)-, (5) —(C1-4 alkylene)-S—(C1-4 alkylene)-,(6) —(C1-4 alkylene)-NR⁸—(C1-4 alkylene)-, (7)-(Cyc2)-(C1-8 alkylene)-,(8) —(C1-8 alkylene)-(Cyc2)- or (9) —(C1-4 alkylene)-(Cyc2)-(C1-4alkylene)-,

R⁸ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenylor (5) C1-8 alkyl substituted by phenyl,

D³ is

(1) a hydrogen atom, (2) —NR⁹R¹⁰, (3) Cyc3, (4) —OR¹¹, (5) COOR, (6)CONR¹³R¹⁴, (7) cyano, (8) a halogen atom, (9) —C(═CR¹⁵)NR¹⁶R¹⁷ or (10)—NR¹⁸C(═NR¹⁹)NR²⁰R²¹,

R⁹ and R¹³ are each independently

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl,(5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8 alkynyloxy or(9) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano,hydroxy or 1 to 3 halogen atom(s),

R¹⁰ and R¹⁴ are each independently

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl,(5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8) C1-8alkoxycarbonyl substituted by Cyc4 or 1 to 3 halogen atom(s), or (9)C1-8 alkyl substituted by C1-8 alkoxy,

R¹¹ and R¹² are each independently

(1) a hydrogen atom or (2) C1-8 alkyl,

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenylor (5) C1-8 alkyl substituted by phenyl,

R⁴ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5)halogen atom, (6) nitro or (7) NR²²R²³,

R²² and R²³ are each independently

(1) a hydrogen atom or (2) C1-8 alkyl,

E¹ is C1-4 alkylene,

E² is

(1) —C(O)NR²⁴—, (2) —NR²⁴C(O)—, (3) —NR²⁴—, (4) —C(O)O— or (5) —S—,

R²⁴ is

(1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted byphenyl,

E³ is

(1) a bond or (2) C1-8 alkylene,

E⁴ is

(1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5)NR²⁵R²⁶, (6) OR²⁷, (7) SR²⁷, (8) COOR²⁷, (9) C1-8 alkyl substituted bytwo of OR²⁵, (10) C1-8 alkyl substituted by 1 to 3 halogen atom(s), (11)cyano or (12) C2-8 acyl,

R²⁵ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl,(5) Cyc5 or (6) C1-8 alkyl substituted by Cyc5 or OR²⁸,

R²⁶ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenylor (5) C1-8 alkyl substituted by phenyl,

R²⁷ is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkylsubstituted by Cyc5,

R²⁸ is

(1) a hydrogen atom or (2) C1-8 alkyl,

G¹ is C1-8 alkylene,

Cyc1 is

(1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or(2) partially or fully saturated 3-10 membered mono- or bi-hetero arylcontaining 1 to 4 hetero atom(s) selected from oxygen, nitrogen andsulfur atoms,

G² is

(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to 2substituent(s) selected from Cyc6, hydroxy and C1-8 alkoxy, (7) C1-8alkoxycarbonyl substituted by Cyc6, (8) —C(O)-Cyc6, (9) nitro, (10)NR⁴¹R⁴², (11) C1-8 alkoxy or (12) C1-8 alkyl substituted by NR⁴¹R⁴²,

R⁴¹ and R⁴² are each dependently

(1) a hydrogen atom or (2) C1-8 alkyl, R⁵ is(1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5)nitro, (6) NR²⁹R³⁰, (7) C1-8 alkyl substituted by NR²⁹R³⁰, (8) NHSO₂OH,(9) amidino, (10) cyano, (11) a halogen atom, (12) Cyc8 or (13) C1-8alkyl substituted by Cyc8,

R²⁹ and R³⁰ are each independently

(1) a hydrogen atom or (2) C1-8 alkyl,

Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are each independently

(1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or(2) partially or fully saturated 3-10 membered mono- or bi-hetero arylcontaining 1 to 4 hetero atom(s) selected from oxygen, nitrogen andsulfur atoms,

Cyc7 is

(1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or(2) partially or fully saturated 3-10 membered mono- or bi-hetero arylcontaining 1 to 4 hetero atom(s) selected from oxygen, nitrogen andsulfur atoms, with proviso that Cyc7 is not benzene,

Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are optionally substituted by 1 to3 substituent(s) selected from (1) C1-8 alkyl, (2) C2-8 alkenyl, (3)C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethoxy,(7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl substituted by C1-8alkoxy or phenyl, (10) hydroxy and (11) NR²⁹R³⁰;

m and n are each independently 1 or 2,

wherein

(i) when A is A¹ or A², then

is not

(ii) when A is A⁴ and

then

R⁵ is not hydroxy or C1-8 alkoxy,

(iii) when A is A⁵, then

is not

and

(iv) following compounds of (1) to (13) are excepted;

-   (1)    4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one,-   (2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (3)    4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one,-   (4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (5) 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (6) 4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (8) 4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (9)    7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one,-   (10)    4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one,-   (11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (12)    4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one,    or

a pharmaceutically acceptable salt thereof,

(2) a process for preparing thereof, and(3) an agent comprising the same as an active ingredient.

In the specification, C1-8 alkyl means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl or isomeric groups thereof.

In the specification, C2-8 alkenyl means ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl or isomeric groups thereof.

In the specification, C2-8 alkynyl means ethynyl, propynyl, butynyl,pentynyl, hexynyl, heptynyl, octynyl or isomeric groups thereof.

In the specification, C1-8 alkoxy means methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or isomeric groupsthereof.

In the specification, C2-8 alkenyloxy means ethenyloxy, propenyloxy,butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy or isomericgroups thereof.

In the specification, C2-8 alkynyloxy means ethynyloxy, propynyloxy,butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy or isomericgroups thereof.

In the specification, C1-8 alkylthio means methylthio, ethylthio,propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio orisomeric groups thereof.

In the specification, C1-4 alkylene means methylene, ethylene,trimethylene, tetramethylene or isomeric groups thereof.

In the specification, C1-8 alkylene means methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene or isomeric groups thereof.

In the specification, C2-8 alkenylene means ethenylene, propenylene,butenylene, pentenylene, hexenylene, heptenylene, octenylene or isomericgroups thereof.

In the specification, C1-8 alkoxycarbonyl means methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl or isomeric groupsthereof.

In the specification, trihalomethyl is methyl substituted by threehalogen atoms.

In the specification, trihalomethoxy is methoxyl substituted by threehalogen atoms.

In the specification, C2-8 acyl means ethanoyl (acethyl), propanoyl(propionyl), butanoyl (butyryl), pentanoyl (valeryl), hexanoyl,heptanoyl, octanoyl or isomeric groups thereof.

In the specification, C3-8 cycloalkyl means cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

In the specification, halogen means chlorine, bromine, fluorine oriodine.

In the specification, partially or fully saturated C3-10mono-carbocyclic aryl represented by

is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene,cyclodecene, cyclohexadiene, cycloheptadiene, cyclooctadiene etc.

In the specification, partially or fully saturated 3-10 memberedmono-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen,nitrogen and sulfur atoms represented by

means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiaine(dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran),dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane,dioxane, dithiolane, dithiane etc.

In the specification, among partially or fully saturated 3-10 memberedmono- or bi-hetero aryl containing 1 to 4 hetero atoms selected fromoxygen, nitrogen or sulfur atom represented by Cyc1, Cyc2, Cyc3, Cyc4,Cyc5, Cyc6, Cyc7 and Cyc8, 3-10 membered mono- or bi-hetero arylcontaining 1 to 4 hetero atoms selected from oxygen, nitrogen or sulfuratom means, for example, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,diazepine, furan, pyran, oxepine, thiophene, thiaine, thiepine, oxazole,isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine,oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine,thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran,isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene,indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine,pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan,benzothiadiazole, benzotriazole etc.

Also, partially or fully saturated 3-10 membered mono- or bi-hetero arylcontaining 1-4 hetero atoms selected from oxygen, nitrogen or sulfuratom, means aziridine, azetidine, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine,piperidine, dihydropyrazine, tetrahydropyrazine, piperazine,dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepine,tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiaine(dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran),dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole(isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline,isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydro isoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine,dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane,dithiolane, dithiane, dioxaindan, benzodioxane, chroman,benzodithiolane, benzodithiane etc.

The above hetero ring includes N-oxide which is the compound wherenitrogen is oxidized.

In the specification, partially or fully saturated C3-10 mono- orbi-carbocyclic aryl represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6,Cyc7 and Cyc8 is cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene,cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene,cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, pentalene, azulene,perhydroazulene, perhydropentalene, indene, perhydroindene, indan,naphthalene, teterahydronaphthalene or perhydronaphthalene etc.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl, alkylene and alkoxygroup includes straight or branched ones. In addition, isomers on doublebond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generatedfrom asymmetric carbon atom(s) (R—, S—, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, l-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

According to the present invention, unless otherwise indicated and as isapparent for those skilled in the art, symbol

indicates that it is bound to the opposite side of the sheet (namelyα-configuration), symbol

indicates that it is bound to the front side of the sheet (namelyβ-configuration), symbol

indicates that it is α-, β- or a mixture thereof, and symbol

indicates that it is a mixture of α-configuration and β-configuration.

The compound of the present invention can be converted into apharmaceutically acceptable salt by known methods.

The pharmaceutically acceptable salt is preferably water-soluble.

The pharmaceutically acceptable salt means, for example, salts of alkalimetals (potassium, sodium, lithium, etc.), salts of alkaline earthmetals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium,tetrabutylammonium, etc.), salts of organic amines (triethylamine,methylamine, dimethylamine, cyclopentylamine, benzylamine,phenethylamine, piperidine, monoethanolamine, diethanolamine,tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine,etc.), acid-addition salts (inorganic acid salts (hydrochloride,hydrobromate, hydroiodate, sulfate, phosphate, nitrate, etc.), organicacid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate,fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate,etc.), etc.

Furthermore, solvates or solvates of the above alkai (earth) metals,ammonium, organic amines and acid-addition salts of the compound of thepresent invention are included in the pharmaceutically acceptable saltof the present invention.

The solvate is preferably nontoxic and water-soluble. Appropriatesolvate means, for example, solvates such as water, an alcohol solvent(ethanol etc.), etc.

In the specification,

is preferably partially or fully saturated C3-7 mono-carbocyclic aryl,or partially or fully saturated 3-7 membered mono-hetero aryl containing1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atom.Moreover, partially or fully saturated C3-7 mono-carbocyclic aryl, orpartially or fully saturated 3-7 membered mono-hetero aryl is preferablyfollowing compounds;

Partially or fully saturated 3-7 membered mono-hetero aryl containing 1to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms ispreferably following compounds;

In the specification, A is preferably A¹, A² or A³.

In the specification, D¹ is preferably —NR⁶C(O)—, —NR⁶C(S)—, —NR⁶SO₂— or—CH₂—NR⁶—, and more preferably —NR⁶C(O)—.

In the specification, D² is preferably C1-8 alkylene, C2-8 alkenylene,—(C1-4 alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4alkylene)-, —(C1-4 alkylene)-NR⁸—(C1-4 alkylene)- or —(C1-8alkylene)-(Cyc2)-, and more preferably C1-8 alkylene.

In the specification, D³ is preferably —NR⁹R¹⁰ or Cyc3.

In the specification, E¹ is preferably C1-4 alkylene.

In the specification, E² is preferably —C(O)NR²⁴—, —NR²⁴C(O)—, —NR²⁴— or—S—

In the specification, E³ is preferably bond or C1-8 alkylene.

In the specification, E⁴ is preferably Cyc5 or NR²⁵R²⁶.

In the specification, Cyc1 is preferably partially or fully saturated3-10 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selectedfrom oxygen, nitrogen and sulfur atom.

In the specification, when A is A³ or A⁴, at least one of X and Y ispreferably N.

In the specification, when A is A³ or A⁴,

is preferably

Among the compounds of the present invention represented by formula (I),preferred compounds are compounds represented by formula (I-A-1)

(wherein all symbols have the same meanings as described above.),compounds represented by formula (I-A-2)

(wherein all symbols have the same meanings as described above.),compounds represented by formula (I-B-1)

(wherein all symbols have the same meanings as described above.),compounds represented by formula (I-B-2)

(wherein all symbols have the same meanings as described above.),compounds represented by formula (I-C-1)

(wherein all symbols have the same meanings as described above.), andcompounds represented by formula (I-C-2)

(wherein all symbols have the same meanings as described above.).

Concrete compounds of the present invention include compounds shown inTables 1 to 90, compounds described in Examples, and pharmaceuticallyacceptable salts thereof.

In each Table, Me represents methyl group, Et represents ethyl group, Prrepresents propyl group, i-Pr represents isopropyl group, Bu representsbutyl group, c-Pr represents cyclopropyl group, c-Bu representscyclobutyl group, c-Pen represents cyclopentyl group, c-Hex representscyclohexyl group, Ph represents phenyl group, Bn represents benzylgroup, and other symbols have the same meanings as described above.

TABLE 1 (I-A-1-1)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 2 (I-A-1-1)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 3 (I-A-1-1)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 4 (I-A-1-2)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 5 (I-A-1-2)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 6 (I-A-1-2)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 7 (I-A-1-3)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 8 (I-A-1-3)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 9 (I-A-1-3)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 10 (I-A-1-4)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 11 (I-A-1-4)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 12 (I-A-1-4)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 13 (I-A-1-5)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 14 (I-A-1-5)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 15 (I-A-1-5)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 16 (I-A-1-6)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 17 (I-A-1-6)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 18 (I-A-1-6)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 19 (I-A-1-7)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 20 (I-A-1-7)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 21 (I-A-1-7)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 22 (I-A-1-8)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 23 (I-A-1-8)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 24 (I-A-1-8)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 25 (I-A-1-9)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 26 (I-A-1-9)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 27 (I-A-1-9)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 28 (I-A-2-1)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 29 (I-A-2-1)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 30 (I-A-2-1)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 31 (I-A-2-2)

No —D²—D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 32 (I-A-2-2)

No —D²—D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 33 (I-A-2-2)

No —D²—D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 34 (I-A-2-3)

No —D²—D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 35 (I-A-2-3)

No —D²—D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 36 (I-A-2-3)

No —D²—D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 37 (I-A-2-4)

No —D²—D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 38 (I-A-2-4)

No —D²—D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 39 (I-A-2-4)

No —D²—D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 40 (I-A-2-5)

No —D²—D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 41 (I-A-2-5)

No —D²—D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 42 (I-A-2-5)

No —D²—D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 43 (I-A-2-6)

No —D²—D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 44 (I-A-2-6)

No —D²—D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 45 (I-A-2-6)

No —D²—D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 46 (I-A-2-7)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 47 (I-A-2-7)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 48 (I-A-2-7)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 49 (I-A-2-8)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 50 (I-A-2-8)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 51 (I-A-2-8)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 52 (I-A-2-9)

No -D²-D³ 1 Me 2 Pr 3 Bu 4 —CH₂—Cl 5 —(CH₂)₃—OH 6 —(CH₂)₄—OH 7—(CH₂)₃—CO₂H 8 —(CH₂)₃—CO₂Me 9

10

11 —(CH₂)₃—NH₂ 12 —(CH₂)₄—NH₂ 13 —(CH₂)₅—NH₂ 14 —(CH₂)₃—NHMe 15—(CH₂)₄—NHMe 16 —CH₂—NMe₂ 17 —(CH₂)₃—NMe₂ 18 —(CH₂)₄—NMe₂ 19—(CH₂)₄—NH-c-Pr 20 —CH₂—NH-c-Bu 21

22

23

24

25

26

27

28

29

30

TABLE 53 (I-A-2-9)

No -D²-D³ 31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

TABLE 54 (I-A-2-9)

No -D²-D³ 61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

TABLE 55 (I-B-1-1)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 56 (I-B-1-2)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 57 (I-B-1-3)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 58 (I-B-1-4)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 59 (I-B-1-5)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 60 (I-B-1-6)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 61 (I-B-1-7)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 62 (I-B-1-8)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 63 (I-B-1-9)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 64 (I-B-1-10)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 65 (I-B-1-11)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 66 (I-B-1-12)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 67 (I-B-1-13)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 68 (I-B-1-14)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 69 (I-B-1-15)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 70 (I-B-2-1)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 71 (I-B-2-2)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 72 (I-B-2-3)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 73 (I-B-2-4)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 74 (I-B-2-5)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 75 (I-B-2-6)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 76 (I-B-2-7)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 77 (I-B-2-8)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 78 (I-B-2-9)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

TABLE 79 (I-B-2-10)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 80 (I-B-2-11)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 81 (I-B-2-12)

No -E³- -E⁴ 1 —(CH₂)₂— —OH 2 —(CH₂)₂— —OMe 3 —(CH₂)₂— —NH₂ 4 —(CH₂)₂——NHMe 5 —(CH₂)₂— —NHEt 6 —(CH₂)₂— —NHPr 7 —(CH₂)₂— —NH-i-Pr 8 —(CH₂)₂——NMe₂ 9 —(CH₂)₂— —NEt₂ 10 —(CH₂)₂— —NPr₂ 11 —(CH₂)₂— —N(i-Pr)₂ 12—(CH₂)₂— —NHPh 13 —(CH₂)₂— —NHBn 14 —(CH₂)₂— —NH-c-Pr 15 —(CH₂)₂——NH-c-Bu 16 —(CH₂)₂— —NH-c-Pen 17 —(CH₂)₂— —NH-c-Hex 18 —(CH₂)₂——NH—(CH₂)₂—OH 19 —(CH₂)₂— —NHCH(Me)(OH) 20 —(CH₂)₂— —N(Me)(c-Pen) 21—(CH₂)₂— —N(Me)(c-Hex) 22 —(CH₂)₂— —N(Me)(Ph) 23 —(CH₂)₂—

24 —(CH₂)₂—

25 —(CH₂)₂—

26 —(CH₂)₂—

27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₃— —OH 30 —(CH₂)₃— —OMe 31 —(CH₂)₃— —NH₂ 32 —(CH₂)₃— —NHMe 33—(CH₂)₃— —NHEt 34 —(CH₂)₃— —NHPr 35 —(CH₂)₃— —NH-i-Pr 36 —(CH₂)₃— —NMe₂37 —(CH₂)₃— —NEt₂ 38 —(CH₂)₃— —NPr₂ 39 —(CH₂)₃— —N(i-Pr)₂ 40 —(CH₂)₃——NHPh 41 —(CH₂)₃— —NHBn 42 —(CH₂)₃— —NH-c-Pr 43 —(CH₂)₃— —NH-c-Bu 44—(CH₂)₃— —NH-c-Pen 45 —(CH₂)₃— —NH-c-Hex 46 —(CH₂)₃— —NH—(CH₂)₂—OH 47—(CH₂)₃— —NHCH(Me)(OH) 48 —(CH₂)₃— —N(Me)(c-Pen) 49 —(CH₂)₃——N(Me)(c-Hex) 50 —(CH₂)₃— —N(Me)(Ph) 51 —(CH₂)₃—

52 —(CH₂)₃—

53 —(CH₂)₃—

54 —(CH₂)₃—

55 —(CH₂)₃—

56 —(CH₂)₃—

57 —(CH₂)₄— —OH 58 —(CH₂)₄— —OMe 59 —(CH₂)₄— —NH₂ 60 —(CH₂)₄— —NHMe 61—(CH₂)₄— —NHEt 62 —(CH₂)₄— —NHPr 63 —(CH₂)₄— —NH-i-Pr 64 —(CH₂)₄— —NMe₂65 —(CH₂)₄— —NEt₂ 66 —(CH₂)₄— —NPr₂ 67 —(CH₂)₄— —N(i-Pr)₂ 68 —(CH₂)₄——NHPh 69 —(CH₂)₄— —NHBn 70 —(CH₂)₄— —NH-c-Pr 71 —(CH₂)₄— —NH-c-Bu 72—(CH₂)₄— —NH-c-Pen 73 —(CH₂)₄— —NH-c-Hex 74 —(CH₂)₄— —NH—(CH₂)₂—OH 75—(CH₂)₄— —NHCH(Me)(OH) 76 —(CH₂)₄— —N(Me)(c-Pen) 77 —(CH₂)₄——N(Me)(c-Hex) 78 —(CH₂)₄— —N(Me)(Ph) 79 —(CH₂)₄—

80 —(CH₂)₄—

81 —(CH₂)₄—

82 —(CH₂)₄—

83 —(CH₂)₄—

84 —(CH₂)₄—

TABLE 82 (I-B-2-13)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 83 (I-B-2-14)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 84 (I-B-2-15)

No -E¹- -E³-E⁴ 1 —CH₂— Me 2 —CH₂— Et 3 —CH₂— Pr 4 —CH₂— i-Pr 5 —CH₂— Ph6 —CH₂— Bn 7 —CH₂— c-Pr 8 —CH₂— c-Bu 9 —CH₂— c-Pen 10 —CH₂— c-Hex 11—CH₂—

12 —CH₂—

13 —CH₂—

14 —CH₂—

15 —CH₂—

16 —CH₂—

17 —(CH₂)₂— Me 18 —(CH₂)₂— Et 19 —(CH₂)₂— Pr 20 —(CH₂)₂— i-Pr 21—(CH₂)₂— Ph 22 —(CH₂)₂— Bn 23 —(CH₂)₂— c-Pr 24 —(CH₂)₂— c-Bu 25 —(CH₂)₂—c-Pen 26 —(CH₂)₂— c-Hex 27 —(CH₂)₂—

28 —(CH₂)₂—

29 —(CH₂)₂—

30 —(CH₂)₂—

31 —(CH₂)₂—

32 —(CH₂)₂—

33 —(CH₂)₃— Me 34 —(CH₂)₃— Et 35 —(CH₂)₃— Pr 36 —(CH₂)₃— i-Pr 37—(CH₂)₃— Ph 38 —(CH₂)₃— Bn 39 —(CH₂)₃— c-Pr 40 —(CH₂)₃— c-Bu 41 —(CH₂)₃—c-Pen 42 —(CH₂)₃— c-Hex 43 —(CH₂)₃—

44 —(CH₂)₃—

45 —(CH₂)₃—

46 —(CH₂)₃—

47 —(CH₂)₃—

48 —(CH₂)₃—

TABLE 85 (I-C-1-1)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 86 (I-C-1-2)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 87 (I-C-1-3)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 88 (I-C-2-1)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 89 (I-C-2-2)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

TABLE 90 (I-C-2-3)

No -Cyc1-G² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Processes for the Preparation of the Compound of the Present Invention:

The compound represented by formula (I) can be prepared by the followingmethod or the method described in Example.

(1) Among the compounds of the present invention represented by formula(I), a compound in which A represents A¹, and D¹ represents —NR⁶C(O)— or—CH₂—NR⁶C(O)—, i.e., a compound represented by formula (IA-1)

(wherein D¹⁻¹ is —NR⁶C(O)— or —CH₂—NR⁶C(O)—, and other symbols have thesame meanings as described above.) can be prepared by the followingmethod.

The compound represented by formula (IA-1) can be prepared by theamidation of the compounds of formula (II)

(wherein R³¹ is —NHR⁶ or —CH₂—NHR⁶, and R¹⁻¹, R⁴⁻¹ and

are R¹, R⁴ and

respectively. With proviso that, hydroxyl or amino in the grouprepresented by R¹⁻¹, hydroxyl or amino represented by R⁴⁻¹, and amino inthe group represented by

may be protected, if necessary. Other symbols have the same meanings asdefined above.) and a compound represented by formula (III)

HOOC-D²⁻¹-D³⁻¹  (III)

(wherein D²⁻¹ and D³⁻¹ are D² and D³ respectively. With proviso that,amino in the group represented by D²⁻¹, and carboxy, hydroxy, amino,amidino or guanidino in D³⁻¹ may be protected, if necessary.), ifnecessary, followed by removal of the protective group from theresulting product.

The method of amidation is known. For example, it includes the method

(1) an acyl halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide may be carried out, for example, byreacting carboxylic acid with an acyl halide (e.g., oxalyl chloride orthionyl chloride etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether or tetrahydrofuran) or without asolvent at −20° C. to reflux temperature. And then the obtained acylhalide derivative may be reacted with amine in an inert organic solvent(e.g., chloroform, methylene chloride, diethyl ether or tetrahydrofuran)in the presence of tertiary amine (e.g., pyridine, triethylamine,dimethylaniline or dimethylaminopyridine etc.) at 0 to 40° C. As analternative, the obtained acyl halide derivative may be reacted in anorganic solvent (dioxane, tetrahydrofuran) using an alkaline aqueoussolution (e.g., sodium bicarbonate, sodium hydroxide) at 0 to 40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with an acyl halide (e.g., pivaloylchloride, tosyl chloride or mesyl chloride) or an acid derivative (ethylchloroformate or isobutyl chloroformate) in an organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran) orwithout a solvent, in the presence of tertiary amine (e.g., pyridine,triethylamine, dimethylaniline or dimethylaminopyridine) at 0 to 40° C.And then the obtained mixed acid anhydride derivative may be reactedwith amine in an organic solvent (e.g., chloroform, methylene chloride,diethyl ether or tetrahydrofuran), at 0 to 40° C.

(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with amine in an organic solvent (e.g.,chloroform, methylene chloride, dimethylformamide, diethyl ether ortetrahydrofuran) or without a solvent, in the presence or absence oftertiary amine (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC), 1,1′-carbodiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,or 1-propanephosphonic acid cyclic anhydride (PPA)), in the presence orabsence of 1-hydroxybenzothiazole (HOBt), at 0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The removal of the protective group may be carried out by followingmethod.

The reaction for removing the protective group for carboxyl, hydroxyl,amino, amidino or guanidino is well known, including, for example, thefollowing:

(1) alkali hydrolysis,

(2) deprotection under acidic condition,

(3) deprotection through hydrogenolysis,

(4) silyl deprotection.

These methods are explained as follows.

(1) The deprotection through alkali hydrolysis may be effected, forexample, in an organic solvent (e.g., methanol, tetrahydrofuran,dioxane) by the use of an alkali metal hydroxide (e.g., sodiumhydroxide, potassium hydroxide, lithium hydroxide), an alkaline earthmetal hydroxide (e.g., barium hydroxide, calcium hydroxide) or acarbonate (e.g., sodium carbonate, potassium carbonate), or an aqueoussolution thereof or their mixture, at 0 to 40° C.

(2) The deprotection under acidic condition may be effected, forexample, in an organic solvent (e.g., dichloromethane, chloroform,dioxane, ethyl acetate, anisole) with an organic solvent (e.g., aceticacid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonicacid) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid) ortheir mixture (hydrogen bromide/acetic acid), at 0 to 100° C.

(3) The deprotection through hydrogenolysis may be effected, forexample, in a solvent (e.g., ether-type (e.g., tetrahydrofuran, dioxane,dimethoxyethane, diethyl ether), alcohol-type (e.g., methanol, ethanol),benzene-type (e.g., benzene, toluene), ketone-type (e.g., acetone,methyl ethyl ketone), nitrile-type (e.g., acetonitrile), amide-type(e.g., dimethylformamide), water, ethyl acetate, acetic acid, or mixedsolvent of two or more of these), in the presence of a catalyst (e.g.,palladium-carbon, palladium-black, palladium hydroxide, platinum oxide,Raney nickel), in a normal-pressure or increased-pressure hydrogenatmosphere or in the presence of ammonium formate, at 0 to 200° C.

(4) The silyl deprotection may be effected, for example, in awater-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile) bythe use of tetrabutylammonium fluoride, at 0 to 40° C.

The carboxyl-protective group includes, for example, methyl, ethyl,t-butyl and benzyl.

The hydroxyl-protective group includes, for example, methoxymethyl,2-tetrahydropyranyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyland benzyl.

The amino, amidino and guanidino-protective group includes, for example,benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl,9-fluorenylmethoxycarbonyl and trimethylsilyl.

The carboxyl, hydroxyl, amino, amidino or guanidino-protective group maybe any others than those mentioned above, capable of being readily andselectively removed, and are not specifically defined. For example,those described in T. W. Greene, Protective Groups in Organic Synthesis,3rd edition, Wiley, New York, 1999 may be used.

The intended compounds of the invention may be readily produced throughselective use of the deprotecting reaction, which could be readilyunderstood by anyone skilled in the art.

(2) Among the compounds of the present invention represented by formula(I), a compound in which A represents A¹, and D¹ represents —NR⁶SO₂—,i.e., a compound represented by formula (IA-2)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-2) can be prepared by thesulfonamidation of the compounds of formula (II-1)

(wherein all symbols have the same meanings as defined above.) and acompound represented by formula (IV)

(wherein R³² is halogen atom and other symbols have the same meanings asdefined above.), if necessary, followed by removal of the protectivegroup from the resulting product.

This sulfonamidation is known. For example, it is carried out at 0 to40° C. in an inert organic solvent (e.g., chloroform, methylenechloride, diethyl ether or tetrahydrofuran) in the presence of tertiaryamine (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine).

The removal of the protective group may be carried out by the abovemethod.

(3) Among the compounds of the present invention represented by formula(I), a compound in which A represents A¹, and D¹ represents —OC(O)—,i.e., a compound represented by formula (IA-3)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-3) can be prepared byesterifying the compounds of formula (V)

(wherein all symbols have the same meanings as defined above.) with theabove compound represented by formula (III)

HOOC-D²⁻¹-D³⁻¹  (III)

(wherein all symbols have the same meanings as defined above.), ifnecessary, followed by removal of the protective group from theresulting product.

The method of esterification is known. For example, it includes themethod

(1) via an acyl halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent.

These methods are explained as follows.

(1) The method via an acyl halide may be carried out, for example, byreacting carboxylic acid with an acyl halide (e.g., oxalyl chloride orthionyl chloride etc.) in an inert organic solvent (e.g., chloroform,methylene chloride, diethyl ether or tetrahydrofuran) or without asolvent at −20° C. to reflux temperature. And then the obtained acylhalide derivative may be reacted with alcohol in an inert organicsolvent (e.g., chloroform, methylene chloride, diethyl ether ortetrahydrofuran) in the presence of tertiary amine (e.g., pyridine,triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0 to40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting carboxylic acid with an acyl halide (e.g., pivaloylchloride, tosyl chloride or mesyl chloride) or an acid derivative (ethylchloroformate or isobutyl chloroformate) in an inert organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran)or without a solvent, in the presence of tertiary amine (e.g., pyridine,triethylamine, dimethylaniline or dimethylaminopyridine) at 0 to 40° C.And then the obtained mixed acid anhydride derivative may be reactedwith alcohol in an inert organic solvent (e.g., chloroform, methylenechloride, diethyl ether or tetrahydrofuran), at 0 to 40° C.

(3) The method using a condensing agent may be carried out, for example,by reacting carboxylic acid with alcohol in an organic solvent (e.g.,chloroform, methylene chloride, dimethylformamide, diethyl ether ortetrahydrofuran) or without a solvent, in the presence or absence oftertiary amine (e.g., pyridine, triethylamine, dimethylaniline ordimethylaminopyridine), using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide(EDC), 1,1′-carbodiimidazole (CDI) or 2-chloro-1-methylpyridiniumiodide), in the presence or absence of 1-hydroxybenzothiazole (HOBt), at0 to 40° C.

The reaction described in (1), (2) and (3) may be carried out under aninert gas (e.g., argon, nitrogen) to avoid water in order to obtain apreferable result.

The removal of the protective group may be carried out by the abovemethod.

(4) Among the compounds of the present invention represented by formula(I), a compound in which A represents A¹, and D¹ represents —CH₂—O—,i.e., a compound represented by formula (IA-4)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-4) can be prepared by theetherification of the compounds of formula (VI-1)

(wherein all symbols have the same meanings as described above.) and thecompound of formula (VII-1)

R³³-D²⁻¹-D³⁻¹  (VII-1)

(wherein R³³ is a leaving group (halogen atom, mesyloxy or tosyloxy,etc.) and other symbols have the same meanings as described above.), ifnecessary, followed by removal of the protective group, by theetherification of the compounds of formula (VI-2)

(wherein all symbols have the same meanings as described above.) and thecompound of formula (VII-2)

HO-D²⁻¹-D³⁻¹  (VII-2)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protective group, or by theetherification of the above compounds of formula (VI-1)

(wherein all symbols have the same meanings as described above.) and thecompound of formula (VII-2)

HO-D²⁻¹-D³⁻¹  (VII-2)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protective group.

This etherification of the compound of formula (VI-1) and the compoundof formula (VII-1), and the compound of formula (VI-2) and the compoundof formula (VII-2) is known. For example, it is carried out at 0 to 100°C. in an inert organic solvent (e.g., dimethylformamide,dimethylsulfoxide, chloroform, methylene chloride, diethyl ether ortetrahydrofuran) in the presence of an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, lithium hydroxide), an alkalineearth metal hydroxide (e.g., barium hydroxide, calcium hydroxide) or acarbonate (e.g., sodium carbonate, potassium carbonate), or an aqueoussolution thereof or their mixture.

This etherification of the compound of formula (VI-1) and the compoundof formula (VII-2) is known. For example, it is carried out at 0 to 60°C. by reacting with a corresponding alcohol compound in an organicsolvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile,benzene, toluene, etc.) in the presence of an azo compound (diethylazodicarboxylate, diisopropyl azodicarboxylate,1,1′-(azodicarbonyl)dipiperidine, 1,1′-azobis(N,N-dimethylformamide),etc.) and a phosphine compound (triphenylphosphine, tributylphosphine,trimethylphosphine, etc.).

The deprotection reaction of the protective group may be carried out bythe methods described above.

(5) Among the compounds of the present invention represented by formula(I), a compound in which A represents A¹, and D¹ represents —NR⁶—, i.e.,a compound represented by formula (IA-5)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-5) can be prepared by reactingthe above compound of formula (II-1)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (VIII-1)

R³²-D²⁻¹-D³⁻¹  (VIII-1)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group, or by reactingthe compound of formula (IX)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (VIII-2)

R⁶HN-D²⁻¹-D³⁻¹  (VIII-2)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

This reaction of the compound of formula (II) and the compound offormula (VIII-1), and the compound of formula (IX) and the compound offormula (VIII-2) is known. For example, it is carried out at 0 to 100°C. in an inert organic solvent (e.g., dimethylformamide,dimethylsulfoxide, chloroform, methylene chloride, diethyl ether,tetrahydrofuran or acetonitrile) in the presence or absence of a base(e.g., triethylamine, pyridine).

The deprotection reaction of the protective group may be carried out bythe methods described above.

Among the compounds of the present invention represented by formula(IA-5), a compound in which D² is C1-8 alkylene, C2-8 alkenylene, —(C1-4alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4 alkylene)-,—(C1-4 alkylene)-NR⁸—(C1-4 alkylene)-, —(C1-8 alkylene)-(Cyc2)- or—(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-, i.e., a compound representedby formula (IA-5-1)

(wherein D^(2′) is C1-8 alkylene, C2-8 alkenylene, —(C1-4alkylene)-O—(C1-4 alkylene)-, —(C1-4 alkylene)-S—(C1-4 alkylene)-,—(C1-4 alkylene)-NR⁸—(C1-4 alkylene)-, —(C1-8 alkylene)-(Cyc2)- or—(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)- and other symbols have the samemeanings as described above.) can be prepared by reductive amination ofthe above compound of formula (II-1)

(wherein all symbols have the same meanings as described above.) and thecompound of formula (VIII-3)

OHC-D^(2″-D) ³⁻¹  (VIII-3)

(wherein D^(2″) is C1-7 alkylene, C2-7 alkenylene, —(C1-3alkylene)-O—(C1-4 alkylene)-, —(C1-3 alkylene)-S—(C1-4 alkylene)-,—(C1-3 alkylene)-NR⁸—(C1-4 alkylene)-, —(C1-7 alkylene)-(Cyc2)- or—(C1-3 alkylene)-(Cyc2)-(C1-4 alkylene)- and other symbols have the samemeanings as described above.), if necessary, followed by removal of theprotecting group.

The reductive amination is well known. For example, it may be carriedout in an organic solvent (e.g., methanol, ethanol) in the presence ofreducing agent (e.g., sodium cyanoborohydride, sodium borohydride,sodium triacetoxyborohydride) and, if necessary, in the presence of anacid (e.g., acetic acid, hydrogen chloride) at −20 to 60° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(6) Among the compounds of the present invention represent by formula(I), a compound in which A is A¹ and D¹ is —CH₂—NR⁶—, i.e., a compoundof formula (IA-6)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-6) can be prepared by reactingthe compound of formula (X)

(wherein all symbols have the same meanings as described above.) withthe above compound of formula (VIII-1)

R³²-D²⁻¹-D³⁻¹  (VIII-1)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group, or by reductiveamination of the compound of formula (XI)

(wherein all symbols have the same meanings as described above.) withthe above compound of formula (VIII-2)

R⁶HN-D²⁻¹-D³⁻¹  (VIII-2)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction of the compound of formula (X) and the compound of formula(VIII-1) may be carried out by the same method as the above reaction ofthe compound of formula (IX) and the compound of formula (VIII-2).

The reaction of the compound of formula (XI) and the compound of formula(VIII-2) may be carried out by the same method as the above reaction ofthe compound of formula (II-1) and the compound of formula (VIII-3).

The removal of the protective group may be carried out by the methodsdescribed above.

(7) Among the compounds represented by formula (I), a compound in whichA is A¹ and D¹ is —NR⁶C(O)NR⁷—, i.e., a compound (IA-7)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-7) can be prepared by reactingthe above compound of formula (II-1)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (XII)

O═C═N-D²⁻¹-D³⁻¹  (XII)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction is known. It may be carried out in organic solvent (e.g.,tetrahydrofuran, methylene chloride, diethyl ether) at 0 to 100° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(8) Among the compounds represented by formula (I), a compound in whichA is A¹ and D¹ is —NR⁶C(S)NR⁷—, i.e., a compound of formula (IA-8)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-8) can be prepared by reactingthe above compound of formula (II-1)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (XIII)

S═C═N-D²⁻¹-D³⁻¹  (XIII)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction is known. It may be carried out in an organic solvent(tetrahydro furan, methylene chloride, diethyl ether) at 0 to 100° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(9) Among the compound of the present invention represented by formula(I), a compound in which A is A¹ and D¹ is —NR⁶C(O)O—, i.e., a compoundof formula (IA-9)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-9) can be prepared by reactingthe above compound of formula (II-1)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (XIV)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction is known. It may be carried out in an organic solvent(e.g., tetrahydrofuran, methylene chloride, diethyl ether) at −78 to 40°C.

The removal of the protective group may be carried out by the methodsdescribed above.

(10) Among the compounds of the present invention represented by formula(I), a compound in which A is A¹ and D¹ is —NR⁶C(S)—, i.e., a compoundof formula (IA-10)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound represented by formula (IA-10) can be prepared bythiocarbonylation of the compound of formula (XV)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction is known. It may be carried out in an organic solvent(e.g., dioxane, benzene, toluene, xylene, tetrahydrofuran), usingLawesson reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) at20 to 150° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(11) Among the compound of the present invention represented by formula(I), a compound in which A is A¹ and D¹ is —NR⁶C(═NR⁷)—, i.e., acompound of formula (IA-11)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IA-11) can be prepared by reacting the abovecompound of formula (II-1)

(wherein all symbols have the same meanings as described above.) withthe compound of formula (XVI)

(wherein R³⁴ is C1-4 alkyl and other symbols have the same meanings asdescribed above.), if necessary, followed by removal of the protectinggroup.

The reaction is known. For example, it may be carried out in an organicsolvent (e.g., methanol, ethanol) at 0 to 50° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(12) Among the compound of the present invention represented by formula(I), a compound in which A is A¹ and D³ is —NR⁹R¹⁰ or hetero ringrepresented by

(among Cyc2, the hetero ring is a hetero ring having at least onenitrogen atom which binds to D²), i.e., a compound of formula (IA-12)

(wherein D³⁻² is —NR⁹R¹⁰ or hetero ring represented by

(among Cyc2, the hetero ring is a hetero ring having at least onenitrogen atom which binds to D² and other symbols have the same meaningsas described above.) can be prepared by the following method.

The compound represented by formula (IA-12) can be prepared by reactinga compound of formula (XVII)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XVIII)

H—NR⁹R¹⁰  (XVIII)

(wherein all symbols have the same meanings as described above.) or acompound of formula (XIX)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction of the compound of formula (XVII) and the compound offormula (XVIII) or (XIX) may be carried out by the same method as theabove reaction of the compound of formula (IX) and the compound offormula (VIII-2).

The removal of the protective group may be carried out by the methodsdescribed above.

(13) Among the compounds of the present invention represented formula(I), a compound in which A is A², and E² is —C(O)NR²⁴—, i.e., a compoundof formula (IB-1)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IB-1) can be prepared by amidation of acompound of formula (XX)

(wherein all symbols have the same meanings as described above.) and thecompound of formula (XXI)

(wherein E⁴⁻¹ is E⁴. With proviso that, hydroxyl, amino or carboxyl inthe group represented by E⁴⁻¹ may be protected, if necessary. Othersymbols have the same meanings as defined above.), if necessary,followed by removal of the protecting group.

The amidation and the removal of the protective group may be carried outby the methods described above.

(14) Among the compounds of the present invention represented by formula(I), a compound in which A is A² and E² is —NR²⁴C(O)—, i.e., a compoundof formula (IB-2)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IB-2) can be prepared by amidation of acompound of formula (XXII)

(wherein all symbols have the same meanings as described above.) and acompound of formula (XXIII)

HOOC-E³-E⁴⁻¹  (XXIII)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The amidation and the removal of the protective group may be carried outby the methods described above.

(15) Among the compounds of the present invention represented by formula(I), a compound in which A is A² and E² is —NR²⁴—, i.e., a compound offormula (IB-3)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IB-3) can be prepared by reacting a compound offormula (XXIV)

(wherein all symbols have the same meanings as described above.) withthe above compound of formula (XXI)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction of the compound of formula (XXIV) and the compound offormula (XXI) may be carried out by the same method as the abovereaction of the compound of formula (IX) and the compound formula(VIII-2).

The removal of the protective group may be carried out by the methodsdescribed above.

(16) Among the compound of the present invention represented by formula(I), a compound in which A is A², and E² is —C(O)O—, i.e., a compound offormula (IB-4)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IB-4) can be prepared by esterifying thecompound of formula (XX)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XXV)

HO-E³-E⁴⁻¹  (XXV)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The esterifying and the removal of the protective group may be carriedout by the methods described above.

(17) Among the compounds of the present invention represented by formula(I), a compound in which A is A², and E² is —S—, i.e., a compound offormula (IB-5)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IB-5) can be prepared by reacting a compound offormula (XXVI)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XXVII)

R³²-E³-E⁴⁻¹  (XXVII)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction is known. For example, it may be carried out in an inertorganic solvent (e.g., dimethylformamide, dimethylsulfoxide, chloroform,methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile) in thepresence or absence of a base (e.g., triethylamine, pyridine) at 0 to100° C.

The removal of the protective group may be carried out by the methodsdescribed above.

(18) Among the compounds of the present invention represented by formula(I), a compound in which A is A², and E⁴ is —NR²⁵R²⁶ or hetero ringrepresented by

(The hetero ring is a hetero ring having at least one nitrogen atom (Thenitrogen atom binds to E³.) in Cyc5.), i.e., a compound of formula(IB-6)

(wherein E⁴⁻² is —NR²⁵R²⁶ or hetero ring represented by

(The hetero ring is a hetero ring having at least one nitrogen atom (Thenitrogen atom binds to E³.) in Cyc5.) and other symbols have the samemeanings as described above.) can be prepared by the following method.

The compound of formula (IB-6) can be prepared by reacting a compound offormula (XXVIII)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XXIX)

H—NR²⁵R²⁶  (XXIX)

(wherein all symbols have the same meanings as described above.) or acompound of formula (XXX)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal of the protecting group.

The reaction of the compound of formula (XXVIII) and the compound offormula (XXIX) or (XXX) may be carried out by the same method as theabove reaction of the compound of formula (IX) and the compound offormula (VIII-2).

The removal of the protective group may be carried out by the methodsdescribed above.

(19) Among the compounds of the present invention represented by formula(I), a compound in which A is A³, i.e., a compound of formula (IC-1)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (IC-1) can be prepared by reacting a compound offormula (XXXI)

(wherein G¹⁻¹ is bond or C1-7 alkylene, Cyc1′ and G²⁻¹ are Cyc1 and G²respectively. With proviso that amino in the group represented by Cyc1,and hydroxy and amino in the group represented by G²⁻¹ may be protected,if necessary. Other symbols have the same meanings as described above.)with hydrazine or a salt thereof (e.g., hydride, chloride), ifnecessary, followed by removal the protecting group.

The reaction is known. For example, it may be carried out in an organicsolvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, aceticacid, tetrahydrofuran) at 50° C. to reflux temperature.

The removal of the protective group may be carried out by the methodsdescribed above.

Moreover, among the compounds of the present invention represented byformula (IC-1), a compound in which Cyc1 is hetero ring represented by

(The hetero ring is a hetero ring having at least one nitrogen atom (Thenitrogen atom binds to G¹.) in Cyc1.), i.e., a compound of formula(IC-1-1)

is a hetero ring having at least one nitrogen atom (The nitrogen atombinds to G¹.) in Cyc1 and other symbols have the same meanings asdescribed above.) can be prepared by following method.

The compound of formula (IC-1-1) can be prepared by reacting a compoundof formula (XXXII)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XXXIII)

(wherein all symbols have the same meanings as described above.), ifnecessary, followed by removal the protecting group.

The reaction of the compound of formula (XXXII) and the compound offormula (XXXIII) may be carried out by the same method as the abovereaction of the compound of formula (IX) and the compound of formula(VIII-2).

The removal of the protective group may be carried out by the methodsdescribed above.

(20) Among the compounds of the present invention represented by formula(I), a compound in which A is A⁴ or A⁵, i.e., a compound of (ID-1)

(wherein A⁶ is A⁴ or A⁵ and other symbols have the same meanings asdescribed above.) can be prepared by the following a) to b).a) The compound of formula (ID-1) can be prepared by reacting a compoundof formula (XXXIV-1)

(wherein R³⁵ is C1-8 alkyl, and A⁶-1 is A⁶. With proviso that hydroxy oramino in the group represented by A⁶⁻¹ may be protected, if necessary.Other symbols have the same meanings as described above.) or a compoundof formula (XXXIV-2)

(wherein all symbols have the same meanings as described above.) withhydrazine or a salt thereof (e.g., hydride, chloride), if necessary,followed by removal the protecting group.

The reaction is known. For example, it may be carried out in an organicsolvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, aceticacid, tetrahydrofuran) at 50° C. to reflux temperature.

The removal of the protective group may be carried out by the methodsdescribed above.

b) The compound of formula (ID-1) can be prepared by reacting a compoundof formula (XXXV)

(wherein all symbols have the same meanings as described above.) withhydrazine and a salt thereof (e.g., hydride, chloride), if necessary,followed by removal the protecting group.

The reaction is known. For example, it may be carried out in an organicsolvent (e.g., methanol, ethanol, propanol, isopropanol, butanol, aceticacid, tetrahydrofuran) at 50° C. to reflux temperature.

The removal of the protective group may be carried out by the methodsdescribed above.

Moreover, among the compound of formula (ID-1), a compound in which X isN,

is single bond, i.e., a compound of formula (ID-1-1)

(wherein all symbols have the same meanings as described above.) can beprepared by the following method.

The compound of formula (ID-1-1) can be prepared by reacting a compoundof formula (XXXVI)

(wherein all symbols have the same meanings as described above.) with acompound of formula (XXXVII)

(wherein R³⁵ has the same meaning as described above.), if necessary,followed by removal of the protecting group.

The reaction may be carried out, for example, in an organic solvent(e.g., toluene, tetrahydrofuran, chloroform, methylene chloride) in thepresence or absence of catalyst (e.g., p-toluenesulfonic acid, pyridine)at 50° C. to reflux temperature.

The removal of the protective group may be carried out by the methodsdescribed above.

The compounds represented by formulae (II), (II-1), (III), (IV), (V),(VI-1), (VI-2), (VII-1), (VII-2), (VIII-1), (VIII-2), (VIII-3), (IX),(X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX),(XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII),(XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV-1), (XXXIV-2), (XXXV),(XXXVI) and (XXXVII) are known compounds or can be prepared by knownmethods or methods as described in Examples.

For example the compounds of formulae (II), (II-1), (V), (VI-1), (VI-2),(IX), (X), (XI), (XX), (XXII), (XXIV), (XXVI), (XXXI), (XXXIV-1),(XXXIV-2), (XXXV) and (XXXVI) can be prepared by the method described inreaction scheme 1, 2, 3 and 4.

In each reaction scheme, R³⁶ is —NHR⁶, —CH₂—NHR⁶, —OH, —CH₂—OH, —CH₂—R³³or halogen atom. With proviso that hydroxy and amino in the grouprepresented by R³⁶ may be protected, if necessary. R³⁷ is the protectinggroup of amino, R³⁸ is —NHR⁶, —CH₂—NHR⁶, —OH, —CH₂—OH, —CH₂—R³³ orhalogen atom, BOP is benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate, Me is methyl, Et is ethyl, E¹⁻¹ is bond or C1-3alkylene, Ph is phenyl, TBAF is tetrabutylammonium fluoride, TMSN₃ istrimethylsilylazide, and R³⁹ is COOH, —NHR²⁴, halogen atom or —SCOCH₃.With proviso that amino or carboxy in the group represented by R³⁹ maybe protected, if necessary. R⁴⁰ is COOH, —NHR²⁴, halogen atom or—SCOCH₃, and other symbols have the same meanings as described above.The compound represented by formulae (XXXIX) and (XXXXXV) with bromoinstead of chloro may be used, which could be readily understood byanyone skilled in the art.

In Reaction Schemes 1, 2, 3 and 4, the compounds used as the startingmaterials are known compounds or can be prepared easily by knownmethods.

In each reaction described herein, the reaction product can be purifiedby general purification techniques such as distillation under ordinarypressure or a reduced pressure, high performance liquid chromatography,thin layer chromatography or column chromatography using silica gel ormagnesium silicate, washing and recrystallization. Purification may becarried out in each reaction or after completion of several reactions.

Pharmacological Activities:

It has been confirmed that the compounds of the present invention offormula (I) have PARP inhibitory activity by the following experimentalresults.

1) Enzyme Assay In Vitro Methods

The below procedure was carried out with 96 well plate at roomtemperature. In a final volume of 80 μL, the reaction mixture containedeach 10 μL of 500 mM Tris/HCl (pH 8.0, WAKO), 100 mM MgCl₂, 50 mMdithiothreitol (sigma), 1 mg/mL activated DNA and 1 mM NAD (containing³H-NAD). The 10 μL of test compound was added to the reaction mixtureand the reaction was started by addition of 10 μL of 0.1 U/μL PARP(TREVIGEN). The reaction was terminated at 10 minutes by addition of 100μL of 20% trichloroacetic acid. Poly(ADP-ribose), which is the reactionproduct, was collected on a glass fiber filter (GF/C, PACKARD). Theradioactivity was measured by topcount (PACKARD). Inhibitory activity ofthe compound was represented by 50% inhibitory concentration calculatedas 100% of control (distilled water). The results were shown in Table91.

TABLE 91 Example No. IC₅₀(μM) 6 (9) 0.61 11 (4) 0.10 30 (4) 0.29

2) Ischemia-Reperfusion Injury Model (Brain and Heart)

Model of cerebral or coronary ischemia-reperfusion was preparedaccording to procedures described previously (Jpn. J. Stroke, 8, 1(1986), Stroke, 27, 1624-1628 (1996) and Eur. J. Pharmacol., 270, 45(1994)). The compounds of the present invention were improvementeffective of these diseases.

Toxicity:

The toxicity of the compounds of the present invention represented byformula (I) is very low (For example, as a result of administering thecompounds of the present invention to rats, they did not affectcirculatory parameters, such as blood pressure, an electrocardiogram,and heart rate.) and therefore the compounds may be considered safe forpharmaceutical use.

INDUSTRIAL APPLICABILITY Application to Pharmaceutical

Since the compound of the present invention represented by formula (I)has PARP inhibitory activity, it is useful for prevention and/ortreatment of various diseases, for example, ischemic diseases (cerebralinfarction, myocardial infarction, reperfusion injury or postoperativeinjury etc.), inflammatory diseases (inflammatory bowel disease,multiple sclerosis, arthritis or lung injury etc.), neurodegenerativedisorders (extrapyramidal disease, Parkinson's disease, Alzheimer'sdisease, muscular dystrophy or lumbar spinal canal stenosis etc.),glaucoma, diabetes, diabetic complication, shock, head trauma, spinalcord injury, renal failure or hyperalgesia etc. Moreover, it is usefulas an antiretroviral drug such as an anti HIV drug, a sensitizer ofanticancer therapy or an immunosuppressant.

The compound represented by formula (I) or pharmaceutically acceptablesalt thereof may be administered in combination with otherpharmaceutical preparations to accomplish the following purposes:

1) To complement for and/or enhance the preventive and/or treatmenteffect of the compound to be combined;2) To improve the kinetics/absorption of the compound to be combined andreduce the dose of the compound; and/or3) To eliminate the side effect of the compound to be combined

The compound represented by formula (I) and other pharmaceuticalpreparations may be administered in the form of formulation having thesecomponents incorporated in one preparation or may be administered inseparate preparations. In the case where these pharmaceuticalpreparations are administered in separate preparations, they may beadministered simultaneously or at different times. In the latter case,the compound represented by formula (I) may be administered before theother pharmaceutical preparations. Alternatively, the otherpharmaceutical preparations may be administered before the compoundrepresented by formula (I). The method for the administration of thesepharmaceutical preparations may be the same or different.

The diseases on which the preventive and/or treatment effect of theaforementioned combined preparations works are not specifically limitedbut may be those for which the preventive and/or treatment effect of thecompound represented by formula (I) is complemented and/or enhanced.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on ischemic diseases include radicalscavenger, astrocyto modulator, N-methyl-D-aspartate (NMDA) antagonist,alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) antagonist,antithrombotic agent, thrombolytic agent, immunosuppressive agent, celladhesion molecules inhibitor, nitrogen oxide synthase (NOS) inhibitor,neurotrophic factor and interleukin-8 inhibitor etc.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) on lumbar spinal canal stenosis includenitrogen oxide synthase (NOS) inhibitor, aldose reductase (AR)inhibitor, radical scavenger, N-methyl-D-aspartate (NMDA) antagonist,alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) antagonist,neurotrophic factor and interleukin-8 inhibitor etc.

Examples of the radical scavenger include, for example, edaravone andebselen (DR-3305) etc.

Examples of the astrocyto modulator include, for example, ONO-2506 etc.

Examples of the antithrombotic agent include, for example, sodiumozagrel, argatroban and aspirin etc.

Examples of the thrombolytic agent include, for example, tissueplasminogen activator (t-PA), urokinase and heparin etc.

Examples of the immunosuppressive agent include, for example,cyclosporin A, cyclophosphamide and tacrolimus etc.

Examples of the NOS inhibitor include, for example, L-NMMA and ONO-1714etc.

Examples of the AR inhibitor include, for example, epalrestat,zenarestat, fidarestat, zopolrestat and AS-3201 etc.

The weight proportion of the compound represented by formula (I) and theother pharmaceutical preparations is not specifically limited.

Arbitrary two or more of the other pharmaceutical preparations may beadministered in combination.

Examples of the other pharmaceutical preparations for complementingand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I) include not only those which have so far beenfound but also those which will be found on the basis of theaforementioned mechanism.

In order to use the compound of the present invention represented byformula (I) or the pharmaceutically acceptable salt thereof, or thecompound represented by formula (I) in combination with the otherpharmaceutical preparations, these compounds are normally administeredto the entire or local part of human body orally or parenterally.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 1 mg to 100 mg, byparenteral administration (preferably intravenous administration), up toseveral times per day, or continuous administration from 1 to 24 hoursper day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compound represented by formula (I) or the pharmaceuticallyacceptable salt thereof, or the concomitant drug combined the compoundrepresented by formula (I) with pharmaceutical preparations may beadministered in the form of, for example, solid compositions, liquidcompositions or other compositions each for oral administration, orinjections, preparations for external use or suppositories, each forparenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, powders, and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more of the active substance(s) maybe admixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone or magnesium aluminometasilicate. The compositionsmay comprise, in accordance with the conventional process, additivesother than the inert diluent, for example, lubricants such as magnesiumstearate, disintegrants such as cellulose calcium glycolate, stabilizersuch as lactose, and solubilizing agent such as glutamic acid oraspartic acid. Tablets or pills may be coated with a film of a gastricsoluble or enteric substance such as sucrose, gelatin, hydroxypropylcellulose or hydroxypropyl methylcellulose phthalate, or with two ormore layers, if necessary. Furthermore, capsules made of a substancewhich can be absorbed in the body, for example, gelatin, are included.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, syrups and elixirs etc. Such liquidcompositions comprise one or more of the active substance(s) and anordinarily employed inert diluent(s) (for example, purified water orethanol) dissolving the substance(s) therein. The compositions maycomprise, in addition to the inert diluent, an adjuvant such ashumectants or suspending agents, sweetening agents, flavoring agents,aromatic agents and antiseptics.

The other compositions for oral administration include sprays whichcomprise one or more active substance(s) and are formulated in a mannerknown per se in the art. The compositions may comprise, in addition toan inert diluent, a stabilizer such as sodium bisulfite and anisotonization buffer such as sodium chloride, sodium citrate or citricacid. The preparation process of sprays is described in detail in, forexample, U.S. Pat. Nos. 2,868,691 and 3,095,355.

In the present invention, injections for parenteral administrationinclude sterile aqueous and/or non-aqueous solutions, suspensions andemulsions. The aqueous solutions or suspensions include, for example,distilled water for injection and saline. The non-aqueous solutions orsuspensions include propylene glycol, polyethylene glycol, vegetableoils such as olive oil, alcohol such as ethanol and Polysorbate 80(trade mark). Furthermore, sterile aqueous and non-aqueous solutions,suspensions, and emulsions may be used in combination. Such compositionsmay additionally comprise adjuvants such as antisaptic, humectant,emulsfier, dispersant, stabilizer (such as lactose) and solubilizingagent (such as glutamic acid and aspartic acid). They are sterilized byfiltration through a bacteria retaining filter, the addition of asterilizer, or irradiation. Also, a sterile solid composition isprepared and then, for example, a freeze-dried product may be dissolvedin sterilized or sterile distilled water for injection or anothersterile solvent before use.

The other compositions for parenteral administration include liquids forexternal use, ointments, endermic liniments, suppositories forintrarectal administration and pessaries for vaginal administrationwhich comprise one or more of the active substance(s) and may beprepared by methods known per se.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained below in detail based on ReferenceExamples and Examples, however, the present invention is not limitedthereto.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC. The solvents in the parentheses in NMR show thesolvents for measurement.

REFERENCE EXAMPLE 13-(3-aminophenyl)-3-methoxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one

To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) intetrahydrofuran (40.0 mL) was added a solution of3-(bis(trimethylsilyl)amino)phenylmagnesium chloride in tetrahydrofuran(1M, 20.0 mL) at −78° C. The mixture was stirred for 1.5 hours. Asaturated aqueous ammonium chloride solution was added to the reactionmixture, which was stirred at room temperature for 30 minutes. Anhydrousmagnesium sulfate was added to the reaction mixture, which wasfiltrated. The filtrate was concentrated to give an oily product.Thionyl chloride (5.20 mL) was added dropwise to methanol (20.0 mL) at−10° C. and then the solution was stirred at 0° C. for 15 minutes. Tothe solution was added the oily product obtained previously and thesolution was stirred at room temperature for 18 hours. The reactionmixture was concentrated. The obtained residue was dissolved inmethylene chloride (20 mL) and thereto was added triethylamine (2.79 mL)at 0° C. Water was added to the reaction solution, which was extractedwith methylene chloride. The extract was washed with water, a saturatedaqueous sodium hydrogen carbonate solution and brine sequentially, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (ethylacetate:hexane=3:7) to give the title compound (2.56 g) having thefollowing physical data.

NMR (DMSO-d₆): δ 7.03 (t, J=7.8 Hz, 1H), 6.60-6.47 (m, 3H), 5.21 (brs,2H), 3.20 (s, 3H), 2.17-1.60 (m, 8H).

EXAMPLE 1 4-(3-aminophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of the compound prepared in Reference example 1 (2.56 g) andhydrazine monohydrate (503 mg) in ethanol (30.0 mL) was refluxed for 18hours. After cooling the reaction mixture to room temperature, thedeposited crystal was collected by filtration. It was washed with hexaneand dried under reduced pressure. 4N hydrogen chloride in dioxane (0.10mL) was added dropwise to a suspension of the obtained solid (32.0 mg)in methanol (1.00 mL) and the mixture was stirred at room temperaturefor 30 minutes. The reaction mixture was concentrated. The obtainedcrystal was dried under reduced pressure to give the compound of thepresent invention (36.2 mg) having the following physical data.Moreover, the compound was converted to methanesulfonate thereof byconventional method.

Hydrochloride:

TLC: Rf 0.27 (ethyl acetate:hexane=2:1);

NMR (DMSO-d₆): δ 12.95 (s, 1H), 9.40 (brs, 3H), 7.47 (t, J=8.1 Hz, 1H),7.32-7.26 (m, 3H), 2.43-1.59 (m, 8H).

Methanesulfonate:

TLC: Rf 0.55 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.94 (s, 1H), 8.31 (s, 1H), 7.44 (t, J=7.8 Hz, 1H),7.26-7.21 (m, 2H), 7.18 (s, 1H), 2.48-2.34 (m, 4H), 2.31 (s, 3H),1.71-1.60 (m, 4H).

EXAMPLE 2 TO EXAMPLE 2(2)

By the same procedure as described in Reference Example 1→Example 1, ifnecessary, by converting to corresponding salts by conventional method,using 3,4,5,6-tetrahydrophthalic acid anhydride in tetrahydrofuran or acorresponding derivative, and3-(bis(trimethylsilyl)amino)phenylmagnesium chloride or a correspondingderivative, the following compounds of the present invention wereobtained.

EXAMPLE 2 4-(3-aminophenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.50 (methanol:methylene chloride=1:9);

NMR (CD₃OD): δ 7.66-7.58 (m, 2H), 7.51-7.44 (m, 2H), 5.82 (m, 1H), 5.73(m, 1H), 3.21 (m, 1H), 2.74 (s, 3H), 2.72-2.47 (m, 3H), 2.27 (m, 1H),1.92 (m, 1H).

EXAMPLE 2(1)4-(3-aminophenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-oneMethanesulfonate

TLC: Rf 0.47 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 13.01 (br-s, 1H), 7.45 (m, 1H), 7.20-7.09 (m, 3H),2.86-2.80 (m, 2H), 2.58-2.52 (m, 2H), 2.31 (s, 3H), 1.86-1.76 (m, 2H),1.58-1.46 (m, 4H).

EXAMPLE 2(2)4-(3-nitro-4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.24 (ethyl acetate:hexane=1:1);

NMR (DMSO-d₆): δ 13.07 (s, 1H), 8.17 (d, J=1.5 Hz, 1H), 7.86 (d, J=8.4Hz, 1H), 7.80 (dd, J=8.4, 1.5 Hz, 1H), 2.48-2.38 (m, 4H), 1.71-1.58 (m,4H).

REFERENCE EXAMPLE 2 4-(3-nitrobenzoyl)thiomorpholine-3-carboxylic acidethyl ester

To a solution of thiomorpholin-3-ylcarboxylic acid ethyl ester (5.05 g)in methylene chloride (120 mL) were added dimethylaminopyridine (352mg), triethylamine (4.9 mL) and 3-nitrobenzoyl chloride (5.62 g) in icebath and then the mixture was stirred at room temperature overnight. 2Nhydrochloric acid was added to the reaction mixture, which was extractedwith methylene chloride. The extract was wash with a saturated aqueoussodium hydrogen carbonate solution and brine sequentially, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=2:1) togive the title compound (5.91 g) having the following physical data.

TLC: Rf 0.23 (hexane:ethyl acetate=2:1);

NMR (CDCl₃): δ 8.32-8.30 (m, 2H), 7.79-7.62 (m, 2H), 5.78 and 4.57 (m,1H), 4.98-4.93 and 3.84-3.79 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 3.71-3.63and 3.28-3.02 and 2.91-2.70 (m, 4H), 2.61-2.57 and 2.43-2.39 (m, 1H),1.36 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 34-((3-nitrophenyl)carbonothioyl)thiomorpholine-3-carboxylic acid ethylester

To a solution of the compound prepared in Reference example 2 (5.88 g)in toluene (90 mL) was added Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(8.62 g) and the mixture was refluxed for 2 hours. After cooling to roomtemperature, the reaction mixture was filtrated and concentrated. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=4:1) to give the title compound (6.16 g) havingthe following physical data.

TLC: Rf 0.27 (hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 8.24-8.17 (m, 2H), 7.66-7.55 (m, 2H), 6.96-6.93 and4.88-4.86 (m, 1H), 5.96-5.90 and 4.13-4.06 (m, 1H), 4.39-4.32 (m, 2H),3.83-3.73 and 3.59-3.50 (m, 1H), 3.37-3.30 and 3.12-3.07 (m, 1H),3.20-3.14 and 3.02-2.94 (m, 1H), 2.94-2.88 and 2.80-2.71 (m, 1H),2.72-2.64 and 2.49-2.41 (m, 1H), 1.40-1.28 (m, 3H).

EXAMPLE 34-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

To a solution of the compound prepared in Reference example 3 (4.78 g)in ethanol (50 mL) was added hydrazine monohydrate (2.0 mL) and themixture was refluxed overnight. The reaction mixture was cooled to roomtemperature and the precipitate was collected by filtration to give thecompound of the present invention (2.30 g) having the following physicaldata.

TLC: Rf 0.45 (chloroform:methanol=19:1);

NMR (DMSO-d₆): δ 10.65 (s, 1H), 8.30-8.27 (m, 2H), 7.89-7.86 (m, 1H),7.76-7.70 (m, 1H), 4.24 (dd, J=10.8, 2.7 Hz, 1H), 3.49 (dt, J=13.8, 2.7Hz, 1H), 3.17-3.08 (m, 1H), 2.97 (dd, J=13.2, 10.8 Hz, 1H), 2.88-2.82(m, 1H), 2.71 (dt, J=12.6, 2.7 Hz, 1H), 2.32-2.27 (m, 1H).

EXAMPLE 4 TO EXAMPLE 4(32)

By the same procedure as described in Reference example 2→Referenceexample 3→Example 3, using thiomorpholin-3-ylcarboxylic acid ethyl esteror a corresponding derivative, and 3-nitrobenzoyl chloride or acorresponding derivative, the following compounds of the presentinvention were obtained.

EXAMPLE 44-(3-nitrophenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-one

TLC: Rf 0.50 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.48 (s, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.22 (s, 1H),7.86 (d, J=8.1 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (m, 1H), 3.17 (m,1H), 2.87 (m, 1H), 2.10 (m, 1H), 1.86 (m, 1H), 1.43 (m, 4H).

EXAMPLE 4(1)4-phenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.18 (hexane:ethyl acetate=2:1);

NMR (DMSO-d₆): δ 10.53 (s, 1H), 7.50-7.38 (m, 5H), 4.23 (dd, J=9.6, 3.6Hz, 1H), 3.52 (m, 1H), 3.08 (m, 1H), 2.94-2.80 (m, 2H), 2.68 (m, 1H),2.30 (d, J=10.5 Hz, 1H).

EXAMPLE 4(2)(9aR)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.18 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.32 (dd, J=8.1, 1.5 Hz, 1H), 8.27 (s, 1H), 8.14 (br,1H), 7.72 (d, J=8.1 Hz, 1H), 7.66 (t, J=8.1 Hz, 1H), 4.39 (dd, J=10.8,2.7 Hz, 1H), 3.72 (dt, J=14.1, 2.7 Hz, 1H), 3.24 (m, 1H), 3.13 (m, 1H),2.99 (dd, J=14.1, 10.8 Hz, 1H), 2.77 (m, 1H), 2.32 (m, 1H);

[α]_(D)=−71.9 (c, 0.16, MeOH).

EXAMPLE 4(3)4-(4-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.28 (ethyl acetate:hexane=1:1);

NMR (DMSO-d₆): δ 10.69 (s, 1H), 8.28 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4Hz, 2H), 4.26 (dd, J=10.2, 3.0 Hz, 1H), 3.48 (d, J=14.4 Hz, 1H),3.17-2.29 (m, 5H).

EXAMPLE 4(4)4-(3-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.17 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.50 (s, 1H), 7.33 (t, J=8.1 Hz, 1H), 7.00-6.93 (m,3H), 4.20 (dd, J=10.5, 3.0 Hz, 1H), 3.76 (s, 3H), 3.53 (dt, J=13.8, 3.0Hz, 1H), 3.10-3.01 (m, 1H), 2.93-2.78 (m, 2H) 2.73-2.63 (m, 1H),2.32-2.27 (m, 1H).

EXAMPLE 4(5)4-(4-methoxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.50 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 7.40-7.26 (m, 2H), 7.04-6.92 (m, 2H), 4.20 (dd, J=9.3,4.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dt, J=14.1, 2.7 Hz, 1H), 3.06 (m, 1H),2.94-2.78 (m, 2H), 2.68 (m, 1H), 2.30 (m, 1H).

EXAMPLE 4(6)4-(2-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.50 (methylene chloride:methanol=10:1);

NMR (CDCl₃): δ 8.14 (br, 1H), 7.21 (ddd, J=8.4, 7.5, 2.1 Hz, 1H), 7.09(t, J=7.5 Hz, 1H), 6.80 (td, J=7.5, 1.2 Hz, 1H), 6.74 (dd, J=8.4, 1.2Hz, 1H), 4.35 (dd, J=10.5, 3.0 Hz, 1H), 3.72 (dt, J=13.8, 3.0 Hz, 1H),3.14 (m, 1H), 3.08-2.90 (m, 2H), 2.79 (m, 1H), 2.21 (dd, J=13.8, 1.2 Hz,1H).

EXAMPLE 4(7)4-(3-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.27 (methylene chloride:methanol=20:1);

NMR (DMSO-d₆): δ 11.02 (brs, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.28 (s, 1H),7.92 (d, J=8.1 Hz, 1H), 7.76 (t, J=8.1 Hz, 1H), 6.28 (s, 1H), 3.61 (m,2H), 3.16 (m, 2H).

EXAMPLE 4(8)4-phenyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.51 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.89 (s, 1H), 7.45 (m, 5H), 6.24 (s, 1H), 3.60 (m,2H), 3.14 (m, 2H).

EXAMPLE 4(9)4-phenyl-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thiazepin-1(2H)-one

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.57 (br-s, 1H), 7.50-7.40 (m, 5H), 4.29 (dd, J=6.9,4.5 Hz, 1H), 3.44-3.36 (m, 1H), 3.16-3.00 (m, 3H), 2.78-2.70 (m, 2H),1.80-1.64 (m, 1H), 1.55-1.40 (m, 1H).

EXAMPLE 4(10)4-(3-nitrophenyl)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thiazepin-1(2H)-one

TLC: Rf 0.60 (chloroform:methanol=9:1).

EXAMPLE 4(11)4-(3-dimethylaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.50 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 7.21 (dd, J=8.1, 7.2 Hz, 1H), 6.75 (m, 1H), 6.72-6.58(m, 2H), 4.20 (dd, J=10.5, 3.0 Hz, 1H), 3.58 (dt, J=13.8, 2.7 Hz, 1H),3.04 (m, 1H), 2.98-2.76 (m, 2H), 2.90 (s, 6H), 2.68 (m, 1H), 2.30 (m,1H).

EXAMPLE 4(12)(8aR)-4-(3-nitrophenyl)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.39 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 11.07 (s, 1H), 8.33 (m, 2H), 8.02 (d, J=7.8 Hz, 1H),7.76 (t, J=7.8 Hz, 1H), 4.53 (m, 2H), 4.28 (m, 1H), 3.46 (m, 2H).

EXAMPLE 4(13)4-(3-amino-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.44 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 7.41 (dd, J=2.1, 2.1 Hz, 1H), 7.32 (dd, J=2.1, 1.2 Hz,1H), 6.94 (dd, J=2.1, 1.2 Hz, 1H), 6.52 (brs, 1H), 6.01 (brs, 2H), 4.23(dd, J=7.5, 3.0 Hz, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 3.00-2.76 (m, 2H),2.68 (m, 1H), 2.33 (m, 1H).

EXAMPLE 4(14)(9aS)-4-(3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.51 (methylene chloride:methanol=10:1).

EXAMPLE 4(15)(7R,8aS)-7-benzyloxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.55 (s, 1H), 7.50-7.24 (m, 10H), 4.53 (d, J=12.3 Hz,1H), 4.48 (d, J=12.3 Hz, 1H), 4.16 (dd, J=8.7, 7.2 Hz, 1H), 4.09-4.03(m, 1H), 3.54 (dd, J=10.8, 3.0 Hz, 1H), 3.44 (dd, J=10.8, 4.8 Hz, 1H),2.39-2.31 (m, 1H), 2.24-2.15 (m, 1H).

EXAMPLE 4(16a)(7R,8aS)-7-benzyloxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.10 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.73 (s, 1H), 8.31-8.27 (m, 2H), 7.95 (dt, J=7.5, 1.5Hz, 1H), 7.75-7.69 (m, 1H), 7.34-7.24 (m, 5H), 4.53 (d, J=12.0 Hz, 1H),4.50 (d, J=12.0 Hz, 1H), 4.24-4.19 (m, 1H), 4.11-4.04 (m, 1H), 3.57 (dd,J=10.5, 3.0 Hz, 1H), 3.50 (dd, J=10.5, 5.1 Hz, 1H), 2.41-2.33 (m, 1H),2.28-2.19 (m, 1H).

EXAMPLE 4(16b)(7R,8aS)-7-benzyloxy-4-(3-aminophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.51 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.45 (s, 1H), 7.34-7.24 (m, 5H), 7.03 (t, J=7.8 Hz,1H), 6.72 (t, J=1.8 Hz, 1H), 6.60 (dd, J=7.8, 1.8 Hz, 1H), 5.19 (s, 2H),4.53 (d, J=12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H), 4.14-4.01 (m, 2H),3.54 (dd, J=10.8, 2.4 Hz, 1H), 3.46 (dd, J=10.8, 4.8 Hz, 1H), 2.38-2.30(m, 1H), 2.22-2.13 (m, 1H).

EXAMPLE 4(17)4-phenyl-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-one

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.55 (br-s, 1H), 7.53-7.43 (m, 5H), 4.43 (d, J=13.8Hz, 1H), 4.20 (dd, J=12.0, 2.4 Hz, 1H), 4.06 (dd, J=13.8, 2.4 Hz, 1H),3.21 (m, 1H), 2.88 (m, 1H), 2.07 (m, 1H), 1.80 (m, 1H).

EXAMPLE 4(18)4-(3-nitrophenyl)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-one

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.70 (br-s, 1H), 8.40 (m, 1H), 8.33 (m, 1H), 7.96 (m,1H), 7.75 (m, 1H), 4.48 (d, J=14.1 Hz, 1H), 4.24 (dd, J=12.0, 2.1 Hz,1H), 4.14 (dd, J=14.1, 2.1 Hz, 1H), 3.23 (m, 1H), 2.91 (m, 1H), 2.08 (m,1H), 1.86 (m, 1H).

EXAMPLE 4(19)4-(3-nitro-4-methylphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.33 (methylene chloride:methanol=20:1);

NMR (DMSO-d₆): δ 10.97 (brs, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.70 (dd,J=7.8, 1.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 3.61 (m, 2H),3.14 (m, 2H), 2.55 (s, 3H).

EXAMPLE 4(20)4-(3-cyanophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.20 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.10 (br, 1H), 7.75 (dt, J=6.9, 1.8 Hz, 1H), 7.68 (m,1H), 7.62-7.55 (m, 2H), 4.36 (dd, J=11.1, 2.7 Hz, 1H), 3.69 (dt, J=11.1,2.7 Hz, 1H), 3.21 (ddd, J=14.1, 12.0, 2.7 Hz, 1H), 3.12 (dt, J=10.8, 2.4Hz, 1H), 2.96 (dd, J=14.1, 11.1 Hz, 1H), 2.74 (m, 1H), 2.32 (ddd,J=11.1, 4.5, 2.4 Hz, 1H).

EXAMPLE 4(21)4-(3-nitro-4-methylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.59 (chloroform:methanol=9:1).

EXAMPLE 4(22)4-(3-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.63 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 7.56-7.46 (m, 1H), 7.36-7.24 (m, 3H), 4.20 (dd, J=10.2,3.6 Hz, 1H), 3.54-3.44 (m, 1H), 3.16-3.02 (m, 1H), 2.96-2.78 (m, 2H),2.76-2.64 (m, 1H), 2.36-2.24 (m, 1H).

EXAMPLE 4(23)4-(3-nitro-5-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.66 (chloroform:methanol=9:1).

EXAMPLE 4(24)4-(2-methyl-5-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.59 (chloroform:methanol=9:1).

EXAMPLE 4(25)4-(4-nitrophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 11.03 (brs, 1H), 8.32-8.25 (m, 2H), 7.77-7.70 (m, 2H),6.29 (s, 1H), 3.64-3.54 (m, 2H), 3.20-3.12 (m, 2H).

EXAMPLE 4(26)4-(2-methyl-3-nitrophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.49 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.64 (s, 1H), 7.93 (dd, J=7.8, 1.5 Hz, 1H), 7.50-7.40 (m,2H), 4.34 (dd, J=11.1, 2.4 Hz, 1H), 3.41 (dt, J=11.1, 2.7 Hz, 1H),3.24-3.00 (m, 2H), 2.91 (dd, J=13.5, 11.1 Hz, 1H), 2.70-2.40 (m, 4H),2.30-2.26 (m, 1H).

EXAMPLE 4(27)4-(3-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.85 (s, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.08-6.96 (m,3H), 6.23 (s, 1H), 3.77 (s, 3H), 3.64-3.56 (m, 2H), 3.16-3.08 (m, 2H).

EXAMPLE 4(28)4-(3-nitro-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.30 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.92 (s, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.73 (dd, J=8.7,2.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.25 (s, 1H), 3.96 (s, 3H),3.65-3.60 (m, 2H), 3.20-3.15 (m, 2H).

EXAMPLE 4(29)4-benzyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.37 (methylene chloride:methanol=10:1);

NMR (CDCl₃): δ 8.03 (br, 1H), 7.39-7.24 (m, 5H), 4.17 (dd, J=10.8, 2.7Hz, 1H), 3.93 (dt, J=14.4, 2.7 Hz, 1H), 3.06 (ddd, J=14.4, 12.0, 2.7 Hz,1H), 2.89 (dt, J=13.5, 2.7 Hz, 1H), 2.78 (dd, J=13.5, 10.8 Hz, 1H), 2.21(ddd, J=14.4, 12.0, 2.7 Hz, 1H), 2.06 (dq, J=14.4, 2.7 Hz, 1H).

EXAMPLE 4(30)4-3-nitrobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.60 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.61 (s, 1H), 8.20-8.10 (m, 2H), 7.64-7.54 (m, 2H), 6.39(s, 1H), 3.82 (s, 2H), 3.80-3.74 (m, 2H), 2.76-2.72 (m, 2H).

EXAMPLE 4(31)4-phenyl-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-one

TLC: Rf 0.67 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.34 (s, 1H), 7.44-7.34 (m, 5H), 3.86 (dd, J=11.1, 3.0Hz, 1H), 3.20 (dt, J=13.2, 2.1 Hz, 1H), 2.77 (td, J=13.2, 2.1 Hz, 1H),2.06 (m, 1H), 1.85 (m, 1H), 1.49-1.26 (m, 4H).

EXAMPLE 4(32)5-phenyl-2,3-dihydro-7H-[1,3]thiazolo[3,2-d][1,2,4]triazin-8(8aH)-one

TLC: Rf 0.30 (ethyl acetate:hexane=1:1);

NMR (DMSO-d₆): δ 10.99 (s, 1H), 7.48 (m, 5H), 5.39 (s, 1H), 3.97 (ddd,J=12.0, 6.3, 1.2 Hz, 1H), 3.35-3.25 (m, 1H), 2.92 (ddd, J=10.0, 6.3, 1.2Hz, 1H), 2.59-2.48 (m, 1H).

EXAMPLE 54-(3-nitro-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

The compound prepared in Example 4(28) (150 mg) and lithium chloride (59mg) were dissolved in dimethylformamide (2.0 mL) and the mixture wasrefluxed for 16 hours. After cooling to room temperature, to thereaction mixture was added 1N hydrochloric acid. The precipitate wascollected by filtration. It was dried to give the compound of thepresent invention (126 mg) having the following physical data.

TLC: Rf 0.19 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 11.45 (brs, 1H), 10.89 (s, 1H), 7.92 (d, J=2.4 Hz, 1H),7.58 (dd, J=9.0, 2.4 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.24 (s, 1H),3.65-3.60 (m, 2H), 3.20-3.15 (m, 2H).

EXAMPLE 64-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

To a solution of the compound prepared in Example 3 (537 mg) in ethanol(4 mL) was added tin chloride dihydrate (2.07 g) and the mixture wasrefluxed for 30 minutes. After cooling to room temperature, a saturatedaqueous sodium hydrogen carbonate solution was added to the reactionmixture, which was extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate and concentrated. Tomethanol (2 mL) was added the obtained solid (137 mg) and then 4Nhydrogen chloride in dioxane (0.26 mL) was added to the mixture, whichwas stirred at room temperature for 3 hours. The reaction mixture wasconcentrated. The residue was recrystallized from a mixture solvent(isopropanol:ethanol=4:1) to give the compound of the present invention(144 mg) having the following physical data. Moreover, the compound wasconverted to methanesulfonate thereof by conventional method.

Hydrochloride:

TLC: Rf 0.42 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.90-10.70 (br, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.40-7.36(m, 3H), 4.25 (dd, J=10.2, 3.0 Hz, 1H), 3.58-3.49 (m, 1H), 3.14-3.06 (m,1H), 2.96-2.82 (m, 2H), 2.77-2.67 (m, 1H), 2.34-2.30 (m, 1H).

Methanesulfonate:

TLC: Rf 0.36 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.84-10.48 (br, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.25-7.18(m, 3H), 4.24 (dd, J=9.9, 3.3 Hz, 1H), 3.56-3.49 (m, 1H), 3.15-3.05 (m,1H), 2.95-2.81 (m, 2H), 2.75-2.65 (m, 1H), 2.33-2.30 (m, 4H).

EXAMPLE 6(1) TO EXAMPLE 6(19)

By the same procedure as described in Example 6, if necessary, byconverting to corresponding salts by conventional method, using thecompounds prepared in Example 4, 4(2), 4(3), 4(6), 4(7), 4(10), 4(12),4(14), 4(13), 4(18), 4(19), 4(21), 4(23)-4(26), 4(28), 4(30) or 5instead of the compound prepared in Example 3, the following compoundsof the present invention were obtained.

EXAMPLE 6(1)4-(3-aminophenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-onemethanesulfonate

TLC: Rf 0.44 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 10.65 (brs, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13-7.04 (m,3H), 3.93 (m, 1H), 3.26 (d, J=13.2 Hz, 1H), 2.82 (m, 1H), 2.31 (s, 3H),2.07 (m, 1H), 1.86 (m, 1H), 1.46 (m, 4H).

EXAMPLE 6(2)(9aR)-4-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.27 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 10.44 (s, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.57 (d, J=7.5Hz, 1H), 6.53 (s, 1H), 6.47 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.19 (t,J=6.6 Hz, 1H), 3.62 (m, 1H), 3.03 (m, 1H), 2.84-2.80 (m, 2H), 2.66 (m,1H), 2.31 (d, J=13.2 Hz, 1H).

EXAMPLE 6(3)4-(4-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.39 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.87 (brs, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4Hz, 2H), 4.26 (dd, J=10.6, 3.0 Hz, 1H), 3.66 (brd, J=14.1 Hz, 1H),3.16-2.35 (m, 5H), 2.30 (s, 3H).

EXAMPLE 6(4)4-(2-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.22 (methylene chloride:methanol=10:1);

NMR (CDCl₃): δ 8.24 (brs, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 4.34 (dd,J=11.7, 2.7 Hz, 1H), 3.95 (brs, 2H), 3.72 (m, 1H), 3.13 (m, 1H),3.08-2.92 (m, 2H), 2.80 (m, 1H), 2.21 (m, 1H).

EXAMPLE 6(5)4-(3-aminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-oneFree Form:

TLC: Rf 0.31 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.81 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.63 (d, J=7.8Hz, 1H), 6.56 (s, 1H), 6.50 (d, J=7.8 Hz, 1H), 6.21 (s, 1H), 5.28 (s,2H), 3.62 (m, 2H), 3.14 (m, 2H).

Methanesulfonate:

TLC: Rf 0.48 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 10.93 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.19 (m, 3H),6.26 (s, 1H), 3.60 (m, 2H), 3.15 (m, 2H), 2.33 (s, 3H).

EXAMPLE 6(6)4-(3-aminophenyl)-7,8,10,10a-tetrahydro-6H-[1,2,4]triazino[5,4-c][1,4]thiazepin-1(2H)-one

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.47 (br-s, 1H), 7.04 (m, 1H), 6.62-6.52 (m, 3H), 5.21(br-s, 2H), 4.25 (dd, J=6.9, 4.5 Hz, 1H), 3.52-3.42 (m, 1H), 3.14-2.96(m, 3H), 2.76-2.60 (m, 2H), 1.82-1.56 (m, 2H).

EXAMPLE 6(7)(8aR)-4-(3-aminophenyl)-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.56 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 10.81 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.72 (s, 1H),6.63 (m, 2H), 5.25 (s, 2H), 4.50 (d, J=9.3 Hz, 1H), 4.41 (d, J=9.3 Hz,1H), 4.16 (t, J=7.2 Hz, 1H), 3.36 (m, 2H).

EXAMPLE 6(8)(9aS)-4-(3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol=10:1);

NMR (CDCl₃): δ 8.01 (br, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.76-6.69 (m, 2H),6.64 (t, J=1.8 Hz, 1H), 4.33 (dd, J=10.8, 3.0 Hz, 1H), 3.85 (dt, J=10.8,3.0 Hz, 1H), 3.78 (br, 2H), 3.11 (m, 1H), 3.05 (m, 1H), 2.94 (dd,J=13.5, 10.8 Hz, 1H), 2.74 (m, 1H), 2.25 (m, 1H).

EXAMPLE 6(9)4-(3,5-diaminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.25 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 5.82 (t, J=1.8 Hz, 1H), 5.75 (d, J=1.8 Hz, 2H), 4.86(brs, 4H), 4.15 (dd, J=9.3, 4.2 Hz, 1H), 3.72 (m, 1H), 3.00 (m, 1H),2.84-2.50 (m, 3H), 2.32 (m, 1H).

EXAMPLE 6(10)4-(3-aminophenyl)-9,9a-dihydro-2H-[1,3]thiazino[3,4-d][1,2,4]triazin-1(8H)-onemethanesulfonate

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.61 (br-s, 1H), 7.42 (m, 1H), 7.29-7.16 (m, 3H), 4.45(d, J=13.8 Hz, 1H), 4.21 (dd, J=12.0, 2.4 Hz, 1H), 4.11 (dd, J=13.8, 2.4Hz, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.32 (s, 3H), 2.08 (m, 1H), 1.78(m, 1H).

EXAMPLE 6(11)4-(3-amino-4-methylphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.38 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.88 (s, 1H), 8.30 (s, 1H), 7.26 (d, J=7.8 Hz, 1H),7.09 (s, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.25 (s, 1H), 3.61 (m, 2H), 3.16(m, 2H), 2.32 (s, 3H), 2.24 (s, 3H).

EXAMPLE 6(12)4-(3-amino-4-methylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.42 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 7.40-7.35 (m, 1H), 7.30-7.25 (m, 2H), 4.25 (dd, J=10.2,3.6 Hz, 1H), 3.60-3.50 (m, 1H), 3.20-3.05 (m, 1H), 2.95-2.80 (m, 2H),2.80-2.65 (m, 1H), 2.40-2.25 (m, 7H).

EXAMPLE 6(13)4-(3-amino-5-fluorophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.65 (brs, 1H), 6.55-6.40 (m, 3H), 4.21 (dd, J=10.2,3.3 Hz, 1H), 3.64-3.54 (m, 1H), 3.14-3.02 (m, 1H), 2.94-2.78 (m, 2H),2.76-2.64 (m, 1H), 2.40-2.30 (m, 4H).

EXAMPLE 6(14)4-(2-methyl-5-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.43 (s, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.51 (dd, J=8.1,2.4 Hz, 1H), 6.45 (brs, 1H), 4.20-4.12 (m, 1H), 3.40-3.26 (m, 1H),3.06-2.94 (m, 1H), 2.90-2.70 (m, 2H), 2.58-2.46 (m, 1H), 2.34-2.22 (m,1H), 2.02 (s, 3H).

EXAMPLE 6(15)4-(4-aminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.39 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.85 (brs, 1H), 7.40-7.32 (d, J=8.4 Hz, 2H), 7.12-7.05(d, J=8.4 Hz, 2H), 6.24 (s, 1H), 3.64-3.58 (m, 2H), 3.20-3.12 (m, 2H),2.34 (s, 3H).

EXAMPLE 6(16)4-(2-methyl-3-aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 7.35-7.27 (m, 2H), 7.20 (brs, 1H), 4.34-4.21 (m, 1H),3.26-3.16 (m, 1H), 3.10-2.98 (m, 1H), 2.96-2.78 (m, 2H), 2.58-2.48 (m,1H), 2.34 (s, 3H), 2.32-2.22 (m, 1H), 2.17 (s, 3H).

EXAMPLE 6(17)4-(3-amino-4-methoxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.53 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.86 (s, 1H), 7.24-7.10 (m, 3H), 6.25 (s, 1H), 3.90(s, 3H), 3.65-3.58 (m, 2H), 3.20-3.13 (m, 2H), 2.32 (s, 3H).

EXAMPLE 6(18)4-(3-amino-4-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.14 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.72 (s, 1H), 9.45 (brs, 1H), 6.66 (d, J=7.5 Hz, 1H),6.60 (d, J=2.1 Hz, 1H), 6.42 (dd, J=7.5, 2.1 Hz, 1H), 6.19 (s, 1H), 4.70(brs, 2H), 3.70-3.60 (m, 2H), 3.20-3.10 (m, 2H).

EXAMPLE 6(19)4-3-aminobenzyl-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.29 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.69 (s, 1H), 6.95 (dt, J=1.2, 7.2 Hz, 1H), 6.44-6.32(m, 3H), 6.06 (s, 1H), 5.08 (s, 2H), 3.72-3.64 (m, 2H), 3.58 (s, 2H),2.76-2.66 (m, 2H).

EXAMPLE 7(7R,8aS)-7-hydroxy-4-(3-nitrophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

To a solution of the compound prepared in Example 4(16a) (76 mg) inmethylene chloride (0.5 mL) was added boron tribromide (2 mL; 1.0 M inmethylene chloride) at −40° C. and the mixture was stirred for 1.5hours. To the reaction mixture was added sodium hydrogen carbonate (ca 1g). The reaction mixture was allowed to return to room temperatureslowly and then brine was added to the reaction mixture, which wasextracted with methylene chloride. The extract was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (chloroform:methanol=19:1→9:1) to give thecompound of the present invention (57 mg) having the following physicaldata.

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.69 (s, 1H), 8.30-8.27 (m, 2H), 7.99-7.96 (m, 1H),7.76-7.71 (m, 1H), 5.21 (d, J=3.6 Hz, 1H), 4.22-4.13 (m, 2H), 3.40 (d,J=3.6 Hz, 2H), 2.17-2.12 (m, 2H).

EXAMPLE 8(7R,8aS)-7-hydroxy-4-(3-aminophenyl)-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-onemethanesulfonate

To a solution of the compound prepared in Example 4(16b) (188 mg) inmethylene chloride (2 mL) was added aluminum trichloride (153 mg) andthe mixture was stirred at room temperature overnight. Moreover,aluminum trichloride (151 mg) was added to the reaction mixture, whichwas stirred at room temperature for 7 hours. Sodium hydrogen carbonate(ca 1 g), small amount of water and methanol were added, sequentially,to the reaction mixture, which was stirred for 30 minutes. The reactionmixture was filtrated through Celite. The filtrate was concentrated. Theresidue was purified by column chromatography on silica gel(chloroform:methanol=19:1→9:1→4:1). To methanol (1 mL) was added theobtained solid and thereto was added a solution of methanesulfonic acid(42 mg) in methanol (1 mL). The mixture was stirred at room temperaturefor 10 minutes. The reaction mixture was concentrated to give thecompound of the present invention (147 mg) having the following physicaldata.

TLC: Rf 0.17 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.90-10.62 (br, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.34-7.21(m, 3H), 4.24-4.16 (m, 2H), 3.44 (dd, J=10.5, 2.4 Hz, 1H), 3.39 (dd,J=10.5, 4.8 Hz, 1H), 2.32 (s, 3H), 2.16-2.12 (m, 2H).

EXAMPLE 94-(3-aminomethylphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

To a solution of4-((3-chloromethylphenyl)carbonothioyl)thiomorpholine-3-carboxylic acidethyl ester (131 mg; It was prepared by the same procedure as describedin Reference example 2→Reference example 3, using 3-chloromethylbenzoylchloride instead of 3-nitrobenzoyl chloride) in dimethylformamide (1.5mL) was added phthalimide potassium salt (70 mg) and the mixture wasstirred at room temperature overnight. Water was added to the reactionmixture, which was extracted with a mixed solvent (hexane:ethylacetate=1:1). The extract was washed with water and brine sequentially,dried over anhydrous sodium sulfate and concentrated. To a solution ofthe obtained solid in ethanol (2 mL) was added hydrazine monohydrate (92μL) and the mixture was refluxed for 1 hour. After cooling the reactionmixture to room temperature, the precipitate was separated by filtrationand the filtrate was concentrated. The precipitate and the residue werepurified by column chromatography on silica gel(chloroform:methanol:water=8:2:0.2), respectively. To the obtained solidwas added a solution of methanesulfonic acid in methanol (1M, 0.11 mL)and the mixture was concentrated. To the obtained residue was addedethyl acetate and the precipitate was separated by filtration. Theprecipitate was dried under reduced pressure to give the compound of thepresent invention (40 mg) having the following physical data.

TLC: Rf 0.11 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 10.59 (s, 1H), 8.14 (br, 3H), 7.60-7.40 (m, 4H), 4.25(t, J=6.6 Hz, 1H), 4.12-4.02 (m, 2H), 3.52 (m, 1H), 3.12 (m, 1H),2.88-2.83 (m, 2H), 2.72 (m, 1H), 2.30 (m, 1H), 2.28 (s, 3H).

EXAMPLE 104-(3-amino-4-fluorophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

By the same procedure as described in Reference example 2→Example6→Reference example 3 Example 3 using3,4-dihydro-2H-1,4-thiazine-5-carboxylic acid ethyl ester instead ofthiomorpholin-3-ylcarboxylic acid ethyl ester, and3-nitro-4-fluorobenzoyl chloride instead of 3-nitrobenzoyl chloride, thecompound of the present invention having the following physical data.

TLC: Rf 0.41 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.81 (s, 1H), 7.04 (dd, J=11.4, 7.8 Hz, 1H), 6.79 (d,J=7.8 Hz, 1H), 6.55 (m, 1H), 6.22 (s, 1H), 5.34 (s, 2H), 3.61 (m, 2H),3.12 (m, 2H).

EXAMPLE 11 8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

Under an atmosphere of hydrogen, a mixture of8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (100 mg; It was prepared by thesame procedure as described in Reference example 1→Example 1 usingfuro[3,4-b]pyridine-5,7-dione instead of4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium chlorideinstead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride),platinum(IV) oxide (10 mg), 1N hydrochloric acid (0.5 mL) anddimethylformamide (5 mL) was stirred at room temperature for 6 hours.The reaction mixture was filtrated through Celite. The filtrate wasconcentrated. The residue was diluted with ethyl acetate. The dilutedsolution was washed with a saturated aqueous sodium hydrogen carbonatesolution and brine sequentially, dried over anhydrous sodium sulfate andconcentrated. The residue was recrystallized from ethanol to give thecompound of the present invention (42 mg) having the following physicaldata. Moreover, the compound was converted to a corresponding saltthereof by conventional method.

Free Form:

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.11 (br-s, 1H), 7.52-7.40 (m, 5H), 5.72 (br-s, 1H),3.13 (m, 2H), 2.39 (t, J=6.6 Hz, 2H), 1.72 (m, 2H).

Hydrochloride:

TLC: Rf 0.40 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.41 (brs, 1H), 7.52-7.40 (m, 5H), 5.88 (brs, 2H),3.16 (t, J=5.4 Hz, 2H), 2.43 (t, J=6.3 Hz, 2H), 1.73 (tt, J=6.3, 5.4 Hz,2H).

Methanesulfonate:

TLC: Rf 0.39 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.37 (s, 1H), 7.54-7.40 (m, 5H), 4.53 (brs, 2H),3.22-3.08 (m, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.35 (s, 3H), 1.82-1.64 (m,2H).

EXAMPLE 11(1) TO EXAMPLE 11(4)

By the same procedure as described in Example 11, if necessary, byconverting to corresponding salts by conventional method, using acorresponding derivative instead of8-phenylpyrido[2,3-d]pyridazin-5(6H)-one, the following compounds of thepresent invention were obtained.

EXAMPLE 11(1)4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-onemethanesulfonate

TLC: Rf 0.30 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 13.30 (s, 1H), 8.94 (br-s, 2H), 7.55-7.43 (m, 5H), 4.00(s, 2H), 3.37 (t, J=6.0 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.30 (s, 3H).

EXAMPLE 11(2)1-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-4(3H)-one

TLC: Rf 0.29 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.93 (br-s, 1H), 7.52-7.40 (m, 5H), 3.61 (br-s, 2H),2.79 (t, J=5.7 Hz, 2H), 2.32 (m, 2H).

EXAMPLE 11(3)5-phenyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-one

TLC: Rf 0.49 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.51 (br-s, 1H), 7.50-7.36 (m, 5H), 6.69 (br-s, 1H),3.27 (m, 2H), 2.39 (t, J=5.7 Hz, 2H), 1.67 (m, 2H).

EXAMPLE 11(4)8-(3-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneHydrochloride:

TLC: Rf 0.40 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 1.73 (m, 2H) 2.41 (t, J=6.04 Hz, 2H) 3.14 (m, 2H) 5.92(br. s., 1H) 7.37 (m, 3H) 7.52 (m, 1H) 12.23 (br. s., 1H).

Dihydrochloride:

TLC: Rf 0.33 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.60 (brs, 1H), 7.64-7.42 (m, 4H), 6.07 (br, 4H),3.24-3.08 (m, 2H), 2.44 (t, J=6.0 Hz, 2H), 1.84-1.64 (m, 2H).

REFERENCE EXAMPLE 46-methoxymethyl-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one

After washing sodium hydride (103 mg; 62.6% in oil) with hexane, themixture was suspended in dimethylformamide (1.5 mL). A solution of8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (200 mg; It was prepared by thesame procedure as described in Reference example 1→Example 1 usingfuro[3,4-b]pyridine-5,7-dione instead of4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and phenylmagnesium chlorideinstead of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride) indimethylformamide (5.7 mL) was added dropwise to the suspension at 0° C.The mixture was stirred at room temperature for 40 minutes.Methoxymethyl chloride (0.27 mL) was added dropwise to the reactionmixture, which was stirred at room temperature overnight. The reactionmixture was concentrated. The obtained residue was diluted in a mixedsolvent of water and ethyl acetate. The mixture was poured in asaturated aqueous sodium hydrogen carbonate solution and extracted withethyl acetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (269 mg)having the following physical data. The obtained compound was used innext reaction without purification.

TLC: Rf 0.78 (chloroform:methanol=8:1).

REFERENCE EXAMPLE 56-methoxymethyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

Under an atmosphere of argon, to platinum oxide (70 mg) was addeddimethylformamide (1.0 mL). A solution of the compound prepared inReference example 4 (269 mg) in dimethylformamide (8.0 mL) was addeddropwise to the reaction mixture and 1N hydrochloric acid (0.9 mL) wasadded thereto. Under an atmosphere of hydrogen, the mixture was stirredat room temperature for 4 hours. Under an atmosphere of argon, thereaction mixture was filtrated through Celite. The filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (methylene chloride:methanol=40:1→30:1) to give the titlecompound (224 mg) having the following physical data.

TLC: Rf 0.16 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 7.56-7.40 (m, 5H), 5.92 (brs, 1H), 5.23 (s, 2H), 3.29(s, 3H), 3.20-3.06 (m, 2H), 2.43 (t, J=6.0 Hz, 2H), 1.84-1.64 (m, 2H).

REFERENCE EXAMPLE 66-methoxymethyl-1-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

After washing sodium hydride (141 mg; 62.6% in oil) with hexane, themixture was suspended in dimethylformamide (1.0 mL). A solution of thecompound prepared in Reference example 5 (200 mg) in dimethylformamide(6.4 mL) was added dropwise thereto at 0° C. and the mixture was stirredat room temperature for 1 hour. Methyl iodide (0.37 mL) was addeddropwise to the reaction mixture, which was stirred at room temperatureovernight. After adding water to the reaction mixture, it was poured inice water and extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=100:1→50:1) to give the title compound (116 mg) havingthe following physical data.

TLC: Rf 0.23 (hexane:ethyl acetate=1:1).

EXAMPLE 121-methyl-8-phenyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

6N hydrochloric acid (2.4 mL) was added dropwise to a solution of thecompound prepared in Reference example 6 (110 mg) in methanol (1.2 mL),which was stirred at room temperature overnight. 6N hydrochloric acid(2.4 mL) was added dropwise to the reaction mixture, which was stirredat 110° C. overnight. After cooling the reaction mixture to roomtemperature, it was poured in cold water. After neutralizing with 5Nsodium hydroxide solution, the solution was extracted with ethylacetate. The extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was washed with ethylacetate to give the compound of the present invention (39 mg) having thefollowing physical data.

TLC: Rf 0.44 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.50 (s, 1H), 7.58-7.34 (m, 5H), 3.12-3.00 (m, 2H),2.41 (t, J=6.0 Hz, 2H), 2.27 (s, 3H), 1.84-1.66 (m, 2H).

REFERENCE EXAMPLE 7N-methyl-N-methoxy-1-t-butoxycarbonylpiperidine-2-carboxamide

To a solution of 1-t-butoxycarbonylpiperidine-2-carboxylic acid (2.29 g)in methylene chloride (30 mL) were added N,O-dimethylhydroxyaminehydrochloride (1.17 g),benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate(4.87 g, BOP reagent) and triethylamine (4.88 mL) and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated. The residue was diluted with ethyl acetate. The dilutedsolution was washed water, 1N hydrochloric acid, water, a saturatedaqueous sodium hydrogen carbonate solution and brine sequentially, driedover anhydrous sodium sulfate and concentrated to give the titlecompound (2.59 g) having the following physical data.

TLC: Rf 0.54 (hexane:ethyl acetate=3:1);

NMR (CDCl₃): δ 5.30-4.86 (m, 1H), 4.06-3.84 (m, 1H), 3.77 (br-s, 3H),3.56-3.36 (m, 1H), 3.19 (s, 3H), 2.04-1.96 (m, 1H), 1.76-1.32 (m, 14H).

REFERENCE EXAMPLE 8 2-benzoylpiperidine-1-carboxylic acid t-butyl ester

A solution of phenyllithium in cyclohexane-ether (1.06 M, 6.23 mL) wasadded dropwise to a solution of the compound prepared in Referenceexample 7 (1.63 g) in tetrahydrofuran (30 mL) at −25° C. and the mixturewas stirred at −25° C. for 3 hours. The reaction mixture was poured in1M sodium dihydrogen phosphate solution and extracted with ethylacetate. The extract was washed with water and brine sequentially, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=9:1) togive the title compound (850 mg) having the following physical data.

TLC: Rf 0.56 (hexane:ethyl acetate=4:1);

NMR (CDCl₃): δ 7.96-7.84 (m, 2H), 7.66-7.40 (m, 3H), 5.70-5.44 (m, 1H),4.04-3.86 (m, 1H), 3.30-3.08 (m, 1H), 2.20-1.98 (m, 1H), 1.92-1.76 (m,1H), 1.74-1.20 (m, 13H).

REFERENCE EXAMPLE 9 2-benzoylpiperidine hydrochloride

To the compound prepared in Reference example 8 (270 mg) was added 4Nhydrogen chloride-ethyl acetate solution (4 mL) and the mixture wasstirred at room temperature for 15 minutes. The reaction mixture wasconcentrated to give the title compound (211 mg) having the followingphysical data.

TLC: Rf 0.48 (chloroform:methanol:acetic acid=40:10:1);

NMR (DMSO-d₆): δ 9.02 (br-s, 2H), 8.05 (m, 2H), 7.75 (m, 1H), 7.61 (m,2H), 5.09 (dd, J=12.0, 3.0 Hz, 1H), 2.97 (m, 1H), 2.09 (m, 1H),1.82-1.58 (m, 4H), 1.44 (m, 1H).

EXAMPLE 131-phenyl-3,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d][1,2,4]triazin-4-one(compound a) and1-phenyl-3,6,7,8-tetrahydro-4H-pyrido[1,2-d][1,2,4]triazin-4-one(compound b)

The compound prepared in Reference example (199 mg) was separated withethyl acetate and a saturated aqueous sodium hydrogen carbonate solutionand the water layer was extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over anhydrous sodium sulfateand concentrated. The obtained powder was dissolved in toluene (10 mL).Thereto were added hydrazine carboxylic acid ethyl ester (184 mg) andp-toluenesulfonic acid monohydrate (8.4 mg) and the mixture was refluxedovernight. After cooling the reaction mixture to room temperature, itwas diluted in ethyl acetate. The diluted solution was washed with 1Nhydrochloric acid, water and brine sequentially, dried over anhydroussodium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate=2:1→1:1). The morepolar fraction was recrystallized from ethyl acetate to give thecompound a (16.3 mg) having the following physical data. The less polarfraction was recrystallized from a mixed solution of ethyl acetate andhexane (1:1) to give the compound b (13.6 mg) having the followingphysical data.

Compound a:

TLC: Rf 0.30 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.14 (s, 1H), 7.76-7.66 (m, 2H), 7.46-7.34 (m, 3H),4.77 (dd, J=11.7, 2.7 Hz, 1H), 4.18 (m, 1H), 2.72 (m, 1H), 1.88-1.34 (m,6H).

Compound b:

TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.74 (s, 1H), 7.56-7.34 (m, 5H), 4.82 (t, J=4.5 Hz,1H), 3.64 (m, 2H), 2.10 (m, 2H), 1.71 (m, 2H).

EXAMPLE 141-phenyl-3,8,9,9a-tetrahydro-4H-[1,3]thiazino[3,4-d][1,2,4]triazin-4-one

By the same procedure as described in Reference example 7→Referenceexample 8→Reference example 9→Example 13 using3-t-butoxycarbonyl-1,3-thiazinane-4-carboxylic acid instead of1-t-butoxycarbonylpiperidine-2-carboxylic acid, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.48 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.42 (s, 1H), 7.75-7.70 (m, 2H), 7.46-7.38 (m, 3H),5.10 (dd, J=11.4, 2.7 Hz, 1H), 4.90 (dd, J=13.2, 2.7 Hz, 1H), 4.34 (d,J=13.2 Hz, 1H), 3.36 (m, 1H), 2.75 (m, 1H), 1.88-1.62 (m, 2H).

REFERENCE EXAMPLE 10((E)-3-oxo-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-ylidene)acetic acidmethyl ester

A solution of 3,4,5,6-tetrahydrophthalic acid anhydride (3.04 g) and(triphenylphosphoranylidene)acetic acid methyl ester (6.69 g) inchloroform (50.0 mL) was refluxed for 3 hours. After cooling thereaction mixture to room temperature, it was concentrated. The residuewas purified by column chromatography on silica gel (ethylacetate:hexane=1:9→3:7) to give the title compound (1.93 g) having thefollowing physical data.

TLC: Rf 0.71 (ethyl acetate:hexane=1:1);

NMR (CDCl₃): δ 5.92 (s, 1H), 3.76 (s, 3H), 2.81 (m, 2H), 2.38 (m, 2H),1.76 (m, 4H).

EXAMPLE 154-methoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of the compound prepared in Reference example 10 (1.04 g) andhydrazine monohydrate (250 mg) in ethanol (10.0 mL) was refluxed for 18hours. After cooling the reaction mixture to room temperature, it wasconcentrated. The obtained crystal was washed with ethanol and ethylacetate, and dried under reduced pressure to give the compound of thepresent invention (672 mg) having the following physical data.

TLC: Rf 0.45 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.66 (brs, 1H), 3.65 (s, 2H), 3.63 (s, 3H), 2.38 (m,4H), 1.64 (m, 4H).

EXAMPLE 164-(1-ethoxycarbonylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

By the same procedure as described in Reference example 10→Example 15using 2-(triphenylphosphoranylidene)propanoic acid ethyl ester insteadof (triphenylphosphoranylidene)acetic acid methyl ester, the compound ofthe present invention having the following physical data was obtained.

TLC: Rf 0.56 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.67 (brs, 1H), 4.07 (q, J=6.9 Hz, 2H), 3.91 (q, J=6.9Hz, 1H), 2.48-2.33 (m, 4H), 1.65 (m, 4H), 1.33 (d, J=6.9 Hz, 3H), 1.13(t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 114-carboxymethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one

5N sodium hydroxide solution (1.72 mL) was added dropwise to asuspension of the compound prepared in Example 15 (635 mg) in methanol(10.0 mL) in ice bath and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrate. 2N hydrochloric acidwas added to the residue, which was adjusted to pH 2. The depositedcrystal was collected by filtration. It was washed with hexane and driedunder reduced pressure to give the title compound (478 mg) having thefollowing physical data.

TLC: Rf 0.62 (methanol:methylene chloride:acetic acid=2:8:0.1);

NMR (DMSO-d₆): δ 12.62 (brs, 2H), 3.54 (s, 2H), 2.39 (m, 4H), 1.64 (m,4H).

REFERENCE EXAMPLE 11(1)4-(1-carboxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

By the same procedure as described in Reference example 11 using thecompound prepared in Example 16 instead of the compound prepared inExample 15, the title compound having the following physical data wasobtained.

TLC: Rf 0.28 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.64 (s, 1H), 12.48 (brs, 1H), 3.81 (q, J=7.5 Hz, 1H),2.48-2.37 (m, 4H), 1.65 (brs, 4H), 1.32 (d, J=7.5 Hz, 3H).

EXAMPLE 17 TO EXAMPLE 17(1)

By the same procedure as described in Reference example 10→Example15→Example 11, if necessary, by converting to corresponding salts byconventional method, using a corresponding derivative instead of4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, and(triphenylphosphoranylidene)acetic acid ethyl ester instead of(triphenylphosphoranylidene)acetic acid methyl ester, the followingcompounds of the present invention were obtained.

EXAMPLE 178-ethoxycarbonylmethyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.46 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 11.88 (br-s, 1H), 6.32 (br-s, 1H), 4.07 (q, J=7.2 Hz,2H), 3.54 (s, 2H), 3.15 (m, 2H), 2.33 (t, J=6.3 Hz, 2H), 1.69 (m, 2H),1.18 (t, J=7.2 Hz, 3H).

EXAMPLE 17(1)5-ethoxycarbonylmethyl-1,3,4,7-tetrahydropyrido[2,3-d]pyridazin-8(2H)-onehydrochloride

TLC: Rf 0.48 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.60 (br-s, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.75 (br-s,2H), 3.28 (m, 2H), 2.45 (m, 2H), 1.77 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 124-(2-hydroxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The compound prepared in Example 15 (350 mg) was dissolved intetrahydrofuran (8.0 mL). Under an atmosphere of argon, sodiumborohydride (239 mg) was added thereto at 0° C. and the mixture wasrefluxed for 13 hours. After cooling to 0° C., 1N hydrochloric acid wasadded to the reaction mixture, which was adjusted to pH 5. The depositedsolid was collected by filtration. The filtrate was concentrated andextracted with chloroform. The extract was dried over anhydrousmagnesium sulfate and concentrated to give the title compound having thefollowing physical data.

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 3.87 (t, J=6.6 Hz, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.64-2.58(m, 2H), 2.54-2.48 (m, 2H), 1.88-1.70 (m, 4H).

REFERENCE EXAMPLE 134-(2-chloroethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of the compound prepared in Reference example 12 g (2.47g) and pyridine (201 mg) in methylene chloride (60 mL) was added thionylchloride (2.25 g) and the mixture was stirred at room temperature for 20hours. Chloroform and a saturated aqueous sodium hydrogen carbonatesolution were added to the reaction mixture, which was separated. Theorganic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and brine sequentially, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (2.58 g)having the following physical data.

TLC: Rf 0.52 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 3.88 (t, J=7.2 Hz, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.60-2.50(m, 4H), 1.85-1.70 (m, 4H).

REFERENCE EXAMPLE 144-(2-azidoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of the compound prepared in Reference example 13 (106 mg),trimethylsilylazide (86.4 mg) and tetrabutylammonium fluoride (237 mg)in tetrahydrofuran (2.00 mL) was refluxed for 24 hours. The reactionmixture was concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:1) to give thetitle compound (85.0 mg) having the following physical data.

TLC: Rf 0.52 (ethyl acetate:hexane=4:1);

NMR (DMSO-d₆): δ 12.62 (brs, 1H), 3.63 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.9Hz, 2H), 2.48-2.37 (m, 4H), 1.67 (m, 4H).

REFERENCE EXAMPLE 154-(2-aminoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one hydrochloride

Under an atmosphere of hydrogen, a suspension of the compound preparedin Reference example 14 (50.0 mg) and 5% palladium on calcium carbonate(20.0 mg) in ethanol (3.0 mL) was stirred at room temperature for 6hours. The reaction mixture was filtrated through Celite. The filtratewas concentrated. 4N hydrogen chloride-ethyl acetate solution (0.5 mL)was added dropwise to a solution of the obtained solid (44.0 mg) inmethanol (3.0 mL) and the mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated. The residue wasrecrystallized from a mixed solvent of methanol and ethyl acetate togive the title compound (45.9 mg) having the following physical data.

TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.1);

NMR (DMSO-d₆): δ 12.65 (s, 1H), 8.07 (brs, 3H), 3.07 (m, 2H), 2.83 (t,J=7.2 Hz, 2H), 2.44 (m, 2H), 2.38 (m, 2H), 1.66 (m, 4H).

REFERENCE EXAMPLE 164-(2-cyanoethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a suspension of the compound prepared in Reference example 13 (500mg) in tetrahydrofuran (12 mL) were added trimethylsilyl cyanide (0.94mL) and tetrabutylammonium fluoride (1.84 g) and the mixture was stirredat 80° C. overnight. After cooling to room temperature, the reactionmixture was poured in a cold saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The extracted was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography on silica gel (methylenechloride:methanol=20:1). The obtained solid was washed with t-butylmethyl ether to give the title compound (249 mg) having the followingphysical data.

TLC: Rf 0.52 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 2.94-2.72 (m, 4H), 2.60-2.26 (m, 4H),1.78-1.54 (m, 4H).

REFERENCE EXAMPLE 174-(2-carboxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a suspension of the compound prepared in Reference example 16 (130mg) in ethanol (3.2 mL) was added 5N sodium hydroxide solution (0.64 mL)and the mixture was stirred at 90° C. for 1 day. After cooling to 0° C.,the reaction mixture was poured in cold water and washed with ethylacetate. The water layer was neutralized with 2N hydrochloric acid andconcentrated. The residue was washed with water. The solid was washedwater and ether to give the title compound (131 mg) having the followingphysical data.

TLC: Rf 0.36 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.51 (s, 1H), 12.08 (brs, 1H), 2.71 (t, J=6.9 Hz, 2H),2.56 (t, J=6.9 Hz, 2H), 2.54-2.26 (m, 4H), 1.78-1.54 (m, 4H).

EXAMPLE 18 3-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)phenylsulfamicacid pyridine salt

To a suspension of the compound prepared in Example 1 (100 mg) inmethylene chloride (1.5 mL) and dimethylformamide (1.5 mL) was addedsulfur trioxide pyridine complex (144 mg) and the mixture was stirred atroom temperature for 4 hours. The reaction mixture was concentrated. Theresidue was washed with ethyl acetate to give the compound of thepresent invention (160 mg) having the following physical data.

TLC: Rf 0.17 (chloroform:methanol=4:1);

NMR (CD₃OD): δ 8.90-8.78 (m, 2H), 8.59 (dddd, J=7.8, 7.8, 1.5, 1.5 Hz,1H), 8.12-7.98 (m, 2H), 7.48-7.14 (m, 3H), 6.89 (m, 1H), 2.66-2.52 (m,2H), 2.52-2.38 (m, 2H), 1.90-1.60 (m, 4H).

EXAMPLE 194-(3-amidinophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

To a solution of the compound prepared in Example 4(20) (127 mg) indimethylformamide (3 mL) were added sodium hydrosulfide (215 mg) andmagnesium chloride hexahydrate (474 mg) and the mixture was stirred atroom temperature for 3 hours under an atmosphere of argon. To thereaction mixture was added ethyl acetate and the precipitate wasseparated by filtration. The filtrate was wash with water and brinesequentially, dried over anhydrous sodium sulfate and concentrated. To asolution of the obtained solid (277 mg) in acetone (2 mL) was addedmethyl iodide (0.15 mL) and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was concentrated. To the residue wereadded methanol (2 mL) and ammonium acetate (43 mg) and the mixture wasrefluxed for 2 hours. The reaction mixture was concentrated. The residuewas purified by column chromatography on silica gel(chloroform:methanol:water=9:1:0.1→8:2:0.2). The obtained solid waswashed with a mixed solvent of methanol, ethyl acetate and hexane andconverted to methanesulfonate thereof by conventional method to give thecompound of the present invention (149 mg) having the following physicaldata.

TLC: Rf 0.22 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 10.68 (s, 1H), 9.36 (s, 2H), 9.02 (s, 2H), 7.86 (d,J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.69 (t, J=7.8 Hz, 1H), 4.26 (dd,J=8.7, 4.8 Hz, 1H), 3.50 (m, 1H), 3.16 (m, 1H), 2.95-2.84 (m, 2H), 2.71(m, 1H), 2.366 and 2.362 (s, 3H), 2.30 (d, J=13.8 Hz, 1H).

EXAMPLE 204-(3-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

To a solution of the compound prepared in Example 4(4) (175 mg) inmethylene chloride (1.3 mL) was added boron tribromide (1.3 mL; 1.0 M inmethylene chloride) in ice bath and the mixture was stirred at roomtemperature for 5 hours. To the reaction mixture was added borontribromide (1.3 mL; 1.0 M in methylene chloride) and the mixture wasstirred at room temperature overnight. Methanol was added to thereaction mixture, which was concentrated. The residue was washed withmethylene chloride. Water was added thereto and the mixture wasextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous magnesium sulfate and concentrated. The residue wasrecrystallized from acetonitrile to give the compound of the presentinvention (73 mg) having the following physical data.

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.47 (s, 1H), 9.67 (bs, 1H), 7.20 (t, J=7.8 Hz, 1H),6.81-6.73 (m, 3H), 4.19 (dd, J=9.3, 3.9 Hz, 1H), 3.56 (dt, J=14.1, 3.0Hz, 1H), 3.09-2.99 (m, 1H), 2.90-2.79 (m, 2H) 2.69-2.60 (m, 1H),2.33-2.28 (m, 1H).

EXAMPLE 20(1) TO EXAMPLE 20(2)

By the same procedure as described in Example 20 using the compoundprepared in Example 4(5) or 4(27) instead of the compound prepared inExample 4(4), the following compounds of the present invention wereobtained.

EXAMPLE 20(1)4-(4-hydroxyphenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.32 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 9.74 (brs, 1H), 7.24-7.14 (m, 2H), 6.84-6.74 (m, 2H),4.18 (dd, J=8.1, 5.1 Hz, 1H), 3.60 (dt, J=14.1, 2.7 Hz, 1H), 3.05 (m,1H), 2.92-2.78 (m, 2H), 2.68 (m, 1H), 2.31 (m, 1H).

EXAMPLE 20(2)4-(3-hydroxyphenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.83 (s, 1H), 9.70 (s, 1H), 7.24 (t, J=7.8 Hz, 1H),6.88-6.75 (m, 3H), 6.22 (s, 1H), 3.66-3.56 (m, 2H), 3.16-3.06 (m, 2H).

EXAMPLE 21N-(3-(4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)phenyl)ethanimidamidehydrobromide

To a suspension of the compound prepared in Example 1 (60 mg) in ethanol(2.5 mL) was added 2-naphthylmethylethanimidothioate (74 mg) and themixture was stirred at room temperature for 4 hours. Methanol (1.5 mL)and 2-naphthylmethylethanimidothioate (222 mg) were added to thereaction mixture, which was stirred at 75° C. overnight. After coolingto room temperature, the reaction mixture was concentrated. The residuewas purified by column chromatography on silica gel (methylenechloride:methanol=20:1→6:1) to give the compound of the presentinvention (84 mg) having the following physical data.

TLC: Rf 0.24 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.97 (s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.50 (m,1H), 7.44-7.34 (m, 2H), 2.54-2.32 (m, 4H), 2.34 (s, 3H), 1.80-1.50 (m,4H).

EXAMPLE 21(1) TO EXAMPLE 21(3)

By the same procedure as described in Example 21 using the compoundprepared in Example 6, 6(5) or 11(4) instead of the compound prepared inExample 1, the following compounds of the present invention wereobtained.

EXAMPLE 21(1)N-(3-(1-oxo-1,2,6,7,9,9a-hexahydro[1,4]thiazino[4,3-d][1,2,4]triazin-4-yl)phenyl)ethanimidamidehydrobromide

TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 11.13 (br, 1H), 10.60 (s, 1H), 9.43 (br, 1H), 8.56 (br,1H), 7.59 (t, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.8 Hz,1H), 7.36 (s, 1H), 4.24 (dd, J=9.6, 3.9 Hz, 1H), 3.63 (d, J=13.8 Hz,1H), 3.10 (d, J=12.0 Hz, 1H), 2.96-2.82 (m, 2H), 2.72 (m, 1H), 2.32 (s,3H), 2.29 (m, 1H).

EXAMPLE 21(2)N-(3-(1-oxo-1,2,6,7-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-4-yl)phenyl)ethanimidamidehydrobromide

TLC: Rf 0.24 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 10.95 (s, 1H), 9.30 (br, 1H), 8.87 (br, 1H), 8.35 (br,1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.42-7.36 (m, 2H), 6.28 (s, 1H),3.72-3.64 (m, 2H), 3.20-3.12 (m, 2H), 2.30 (brs, 3H).

EXAMPLE 21(3)N-(3-(5-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanimidamide

TLC: Rf 0.14 (chloroform:methanol=4:1).

EXAMPLE 224-(3-methylaminophenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

To a suspension of the compound prepared in Example 6(5) (100 mg) inmethanol (1.1 mL) were added a solution of sodium methylate in methanol(0.5 mL; 28% solution) and paraformaldehyde (32 mg) and the mixture wasstirred at room temperature for 3 hours. Methanol (1.1 mL) and sodiumborohydride (22 mg) were added to the reaction mixture, which wasstirred at 75° C. for 1 hour. After cooling to room temperature, waterwas added to the reaction mixture, which was poured in cold water. Thesolution was concentrated. The residue was washed with a mixed solventof methanol and methylene chloride and filtrated through Celite. Thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=15:1) to givethe compound of the present invention (15 mg) having the followingphysical data.

TLC: Rf 0.44 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 10.80 (s, 1H), 7.15 (dd, J=7.5, 7.5 Hz, 1H), 6.66-6.46(m, 3H), 6.21 (s, 1H), 5.86 (q, J=4.8 Hz, 1H), 3.68-3.56 (m, 2H),3.20-3.06 (m, 2H), 2.67 (d, J=4.8 Hz, 3H).

EXAMPLE 234-(N-(2-(N′-t-butoxycarbonylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The mixture of the compound prepared in Reference example 11 (183 mg),triethylamine (178 mg), N-(2-aminoethyl)carbamic acid t-butyl ester (160mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (338mg), 1-hydroxybenzotriazol (238 mg) and dimethylformamide (3.00 mL) wasstirred at room temperature for 16 hours. The reaction mixture wasconcentrated. To the residue was added water and the deposited crystalwas collected by filtration. It was washed with ethyl acetate and driedunder reduced pressure to give the compound of the present invention(189 mg) having the following physical data.

TLC: Rf 0.50 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 8.01 (brs, 1H), 6.77 (brs, 1H), 3.39 (s,2H), 3.08-2.95 (m, 4H), 2.38 (m, 4H), 2.25 (m, 4H), 1.37 (s, 9H).

EXAMPLE 23(1) TO EXAMPLE 23(37)

By the same procedure as described in Example 23, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 11 or a corresponding carboxylic acidderivative, and N-(2-aminoethyl)carbamic acid t-butyl ester or acorresponding derivative, the following compounds of the presentinvention were obtained.

EXAMPLE 23(1)4-(N-(2-(morpholin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.60 (brs, 1H), 11.06 (brs, 1H), 8.45 (t, J=5.7 Hz,1H), 3.95-3.77 (m, 4H), 3.47 (s, 2H), 3.43 (m, 4H), 3.18-3.02 (m, 4H),2.37 (m, 4H), 1.64 (brs, 4H).

EXAMPLE 23(2)4-(N-(2-(N′,N′-dimethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.60 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.1);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 7.94 (brt, J=6.2 Hz, 1H), 3.40 (s,2H), 3.13 (td, J=6.2, 6.2 Hz, 2H), 2.43 (brs, 2H), 2.36 (brs, 2H), 2.26(t, J=6.2 Hz, 2H), 2.12 (s, 6H), 1.63 (brs, 4H).

Hydrochloride:

TLC: Rf 0.69 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 10.22 (brs, 1H), 8.39 (t, J=5.7 Hz, 1H),3.41-2.98 (m, 4H), 2.24 (m, 8H), 2.48-2.36 (m, 4H), 1.64 (brs, 4H).

EXAMPLE 23(3)4-(N-(3-(N′-t-butoxycarbonylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (DMSO-d₆): δ 12.56 (s, 1H), 7.97 (t, J=5.1 Hz, 1H), 6.75 (m, 1H),3.39 (s, 2H), 3.02 (q, J=6.6 Hz, 2H), 2.90 (q, J=6.6 Hz, 2H), 2.46-2.33(m, 4H), 1.68-1.58 (m, 4H), 1.55-1.44 (m, 2H), 1.36 (s, 9H).

EXAMPLE 23(4)4-(N-(2-(N′-t-butoxycarbonyl-N′-methylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.59 (chloroform:methanol:water=8:2:0.2);

NMR (CDCl₃): δ 10.69 (br, 1H), 6.88 (br, 1H), 3.49 (s, 2H), 3.45-3.32(m, 4H), 2.86 (s, 3H), 2.60-2.48 (m, 4H), 1.90-1.80 (m, 4H), 1.45 (s,9H).

EXAMPLE 23(5)4-(N-(2-(pyrrolidin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.24 (ethyl acetate:acetic acid:water=3:3:1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 10.46 (br, 1H), 8.39 (m, 1H), 3.61-3.50(m, 2H), 3.47 (s, 2H), 3.40 (q, J=6.0 Hz, 2H), 3.17 (q, J=6.0 Hz, 2H),3.04-2.90 (m, 2H), 2.50-2.34 (m, 4H), 2.04-1.90 (m, 2H), 1.90-1.80 (m,2H), 1.70-1.60 (m, 4H).

EXAMPLE 23(6)4-(2-hydroxyethoxycarbonylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 4.80 (t, J=5.1 Hz, 1H), 4.07 (t, J=5.1Hz, 2H), 3.66 (s, 2H), 3.55 (q, J=5.1 Hz, 2H), 2.45-2.34 (m, 4H),1.70-1.60 (m, 4H).

EXAMPLE 23(7)4-(N-(3-(N′,N′-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.12 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 10.43 (br, 1H), 8.28 (m, 1H), 3.42 (s,2H), 3.11 (q, J=6.0 Hz, 2H), 3.04-2.96 (m, 2H), 2.71 (s, 3H), 2.69 (s,3H), 2.46-2.34 (m, 4H), 1.84-1.74 (m, 2H), 1.68-1.48 (m, 4H).

EXAMPLE 23(8)4-(N-(3-(imidazol-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.82 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 14.64 (br, 1H), 12.60 (s, 1H), 9.17 (m, 1H), 8.39 (m,1H), 7.81 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 4.22 (t, J=6.6 Hz,2H), 3.44 (s, 2H), 3.03 (q, J=6.6 Hz, 2H), 2.46-2.32 (m, 4H), 1.93(quin, J=6.6 Hz, 2H), 1.68-1.46 (m, 4H).

EXAMPLE 23(9)4-(1-(N-(2-(N′-t-butoxycarbonylamino)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 7.93 (t, J=5.1 Hz, 1H), 6.74 (brs, 1H),3.66 (q, J=7.2 Hz, 1H), 3.05 (m, 2H), 2.96 (m, 2H), 2.48-2.30 (m, 4H),1.63 (m, 4H), 1.36 (s, 9H), 1.30 (d, J=7.2 Hz, 3H).

EXAMPLE 23(10)4-(N-(1-ethylpyrrolidin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.59 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 10.42 (brs, 1H), 8.56 (m, 1H), 3.58-2.96(m, 9H), 2.42-2.36 (m, 4H), 2.08-1.64 (m, 8H), 1.24 (t, J=6.9 Hz, 3H).

EXAMPLE 23(11)4-(N-(3-(morpholin-4-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.48 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.00 (brt, 1H), 3.64-3.48 (m, 4H),3.46-3.18 (m, 6H), 3.14-2.96 (m, 2H), 2.50-2.14 (m, 6H), 1.74-1.44 (m,6H).

EXAMPLE 23(12)4-(N-(3-(pyrrolidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.25 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 10.59 (br, 1H), 8.25 (br, 1H), 3.52-3.38(m, 4H), 3.17-3.00 (m, 4H), 2.98-2.84 (m, 2H), 2.46-2.32 (m, 4H),2.00-1.75 (m, 6H), 1.69-1.58 (m, 4H).

EXAMPLE 23(13)4-(N-(pyridin-3-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.47 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.67 (s, 1H), 11.31 (s, 1H), 9.12 (d, J=2.1 Hz, 1H),8.55 (d, J=4.8 Hz, 1H), 8.43 (d, J=8.7 Hz, 1H), 7.86 (dd, J=8.7, 4.8 Hz,1H), 3.78 (s, 2H), 2.48-2.39 (m, 4H), 1.65 (brs, 4H).

EXAMPLE 23(14)4-(N-(2-(piperidin-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.53 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 10.30 (br, 1H), 8.44 (br, 1H), 3.50-3.34(m, 2H), 3.31 (s, 2H), 3.10-2.96 (br, 2H), 2.90-2.72 (br, 2H), 2.48-2.32(m, 4H), 1.80-1.68 (br, 4H), 1.68-1.56 (br, 6H), 1.50-1.40 (br, 2H).

EXAMPLE 23(15)4-(N-(2-(N′,N′-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.26 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 10.40 (br, 1H), 8.32 (br, 1H), 3.48 (s,2H), 3.42-3.12 (m, 3H), 2.58 (s, 6H), 2.46-2.32 (m, 4H), 1.68-1.58 (m,4H), 1.12 (d, J=6.0 Hz, 3H).

EXAMPLE 23(16)4-(N-(4-(N′-t-butoxycarbonylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (CD₃OD): δ 8.12 (br, 1H), 6.59 (br, 1H), 3.54 (s, 2H), 3.23-3.15 (m,2H), 3.08-2.98 (m, 2H), 2.56-2.47 (m, 4H), 1.82-1.74 (m, 4H), 1.56-1.46(m, 4H), 1.42 (s, 9H).

EXAMPLE 23(17)4-(N-(pyridin-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.51 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.64 (s, 1H), 11.08 (s, 1H), 8.33 (m, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.87 (m, 1H), 7.18 (m, 1H), 3.77 (s, 2H), 2.45-2.38 (m,4H), 1.65 (brs, 4H).

EXAMPLE 23(18)4-(2-(N′,N′-dimethylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.51 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 4.13 (t, J=5.7 Hz, 2H), 3.64 (s, 2H),2.44 (t, J=5.7 Hz, 2H), 2.44-2.35 (m, 4H), 2.12 (s, 6H), 1.72-1.58 (m,4H).

Hydrochloride:

TLC: Rf 0.51 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.70 (s, 1H), 10.72 (br, 1H), 4.44-4.36 (m, 2H), 3.74(s, 2H), 3.40-3.32 (m, 2H), 2.75 (s, 6H), 2.46-2.32 (m, 4H), 1.72-1.60(m, 4H).

EXAMPLE 23(19)4-(N-(2-(pyrrol-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.11 (m, 1H), 6.69 (d, J=1.2 Hz, 2H),5.96 (d, J=1.2 Hz, 2H), 3.92 (t, J=6.0 Hz, 2H), 3.38 (s, 2H), 3.35 (t,J=6.0 Hz, 2H), 2.40-2.24 (m, 4H), 1.68-1.58 (m, 4H).

EXAMPLE 23(20)4-(N-(2-(imidazol-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.56 (chloroform:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 8.10 (m, 1H), 7.73 (br, 1H), 6.86 (s,1H), 3.39 (s, 2H), 3.34-3.23 (m, 2H), 2.74-2.62 (m, 2H), 2.40-2.30 (m,4H), 1.66-1.56 (m, 4H).

EXAMPLE 23(21)4-(1-(N-(4-(N′-t-butoxycarbonylamino)butyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.38 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 7.93 (t, J=5.7 Hz, 1H), 6.77 (m, 1H),3.66 (q, J=7.0 Hz, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.48-2.26 (m, 4H),1.63 (brs, 4H), 1.42-1.28 (m, 16H).

EXAMPLE 23(22)4-(N-(pyridin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.85 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.62 (t, J=6.0 Hz, 1H), 8.49 (m, 1H),7.75 (dt, J=7.5, 1.8 Hz, 1H), 7.29 (m, 1H), 7.25 (m, 1H), 4.35 (d, J=6.0Hz, 2H), 3.51 (s, 2H), 2.48-2.34 (m, 4H), 1.70-1.58 (m, 4H).

EXAMPLE 23(23)4-(N-(2-bromoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.64 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.32 (m, 1H) 3.52-3.44 (m, 2H), 3.43 (s,2H), 3.42-3.33 (m, 2H), 2.48-2.33 (m, 4H), 2.70-1.60 (m, 4H).

EXAMPLE 23(24)4-(N-(3-bromopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 8.10 (t, J=6.0 Hz, 1H), 3.51 (t, J=6.0Hz, 2H), 3.40 (s, 2H), 3.15 (q, J=6.0 Hz, 2H), 2.45-2.33 (m, 4H), 1.93(quin, J=6.0 Hz, 2H), 1.68-1.59 (m, 4H).

EXAMPLE 23(25)4-(N-(5-(N′-t-butoxycarbonylamino)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (DMSO-d₆): δ 12.56 (s, 1H), 7.99 (t, J=6.0 Hz, 1H), 6.75 (t, J=6.0Hz, 1H), 3.38 (s, 2H), 3.10 (q, J=6.0 Hz, 2H), 2.86 (q, J=6.0 Hz, 2H),2.45-2.33 (m, 4H), 1.69-1.62 (m, 4H), 1.44-1.29 (m, 4H), 1.36 (s, 9H),1.28-1.18 (m, 2H).

EXAMPLE 23(26)4-(N-(5-methylthiazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.57 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.65 (brs, 1H), 12.12 (brs, 1H), 7.12 (s, 1H), 3.73(s, 2H), 2.39 (m, 4H), 2.32 (s, 3H), 1.65 (brs, 4H).

EXAMPLE 23(27)4-(N-(3-(N′,N′-dimethylamino)propyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.11 (methylene chloride:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 10.92 and 10.51 (br, 1H), 3.68 and 3.66(s, 2H), 3.43 and 3.36 (t, J=6.6 Hz, 2H), 3.80-2.90 (m, 2H), 3.01 and2.82 (s, 3H), 2.73 and 2.71 and 2.69 (s, 6H), 2.42-2.32 (m, 4H),2.02-1.82 (m, 2H), 1.67-1.58 (m, 4H).

EXAMPLE 23(28)4-(N-(2-(N′,N′-dimethylamino)ethyl)-N-methylcarbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.21 (methylene chloride:methanol:water=7:3:0.3);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 10.69 and 9.93 (br, 1H), 3.75 and 3.68(s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (q, J=6.0 Hz, 2H), 3.04 and 2.84(s, 3H), 2.79 and 2.77 and 2.76 (s, 6H), 2.42-2.33 (m, 4H), 1.68-1.60(m, 4H).

EXAMPLE 23(29)4-(N-(4-bromobutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.65 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 8.02 (t, J=6.3 Hz, 1H), 3.52 (t, J=6.3Hz, 2H), 3.39 (s, 2H), 3.06 (q, J=6.3 Hz, 2H), 2.45-2.33 (m, 4H),1.82-1.73 (m, 2H), 1.67-1.58 (m, 4H), 1.58-1.48 (m, 2H).

EXAMPLE 23(30)4-(2-(N-t-butoxycarbonylamino)ethoxycarbonylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (CD₃OD): δ 4.15 (t, J=5.7 Hz, 1H), 3.71 (m, 2H), 3.54 (t, J=5.7 Hz,2H), 3.29 (t, J=5.7 Hz, 1H), 3.14 (t, J=5.7 Hz, 1H), 2.56-2.47 (m, 4H),1.91-1.84 (m, 4H), 1.43 (s, 9H).

EXAMPLE 23(31)4-(N-(4-oxo-4,5-dihydro-1,3-thiazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (DMSO-d₆): δ 12.73 (brs, 1H), 12.67 (s, 1H), 3.88 (s, 2H), 3.80 (s,2H), 2.38 (brs, 4H), 1.65 (brs, 4H).

EXAMPLE 23(32)4-(N-(1-methyl-4-oxo-1,5-dihydro-4H-imidazol-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.49 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.52 (brs, 1H), 11.03 (brs, 1H), 4.00 (s, 2H), 3.58(s, 2H), 2.90 (s, 3H), 2.41 (m, 4H), 1.63 (brs, 4H).

EXAMPLE 23(33)4-(2-(N-(2-(N′-t-butoxycarbonylamino)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.66 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.50 (s, 1H), 7.87 (brt, 1H), 6.78 (brt, 1H),3.12-2.84 (m, 4H), 2.78-2.62 (m, 2H), 2.56-2.26 (m, 6H), 1.76-1.54 (m,4H), 1.36 (s, 9H).

EXAMPLE 23(34)4-(N-(2-cyanoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.79 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.39 (t, J=5.7 Hz, 1H), 3.43 (s, 2H),3.32-3.23 (m, 2H), 2.64 (t, J=6.3 Hz, 2H), 2.45-2.33 (m, 4H), 1.68-1.60(m, 4H).

EXAMPLE 23(35)4-(N-(4-(imidazol-1-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.75 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s 1H), 8.03 (m, 1H), 7.60 (s, 1H), 7.13 (s, 1H),6.87 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 3.38 (s, 2H), 3.05 (q, J=6.6 Hz,2H), 2.46-2.33 (m, 4H), 1.74-1.60 (m, 6H), 1.31 (quin, J=6.6 Hz, 2H).

EXAMPLE 23(36)4-(N-(2-methoxycarbonylethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.83 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s 1H), 8.13 (m, 1H), 3.58 (s, 3H), 3.38 (s, 2H),3.32-3.24 (m, 2H), 2.50-2.43 (m, 2H), 2.42-2.32 (m, 4H), 1.68-1.60 (m,4H).

EXAMPLE 23(37)4-(N-methyl-N-(3-chloropropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.81 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 3.68 and 3.60 (m, 2H), 3.63 and 3.31 (s,2H), 3.45 and 3.41 (t, J=6.3 Hz, 2H), 3.02 and 2.81 (s, 3H), 2.41-2.33(m, 4H), 2.01 and 1.90 (m, 2H), 1.70-1.60 (m, 4H).

EXAMPLE 244-(N-(2-hydroxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A mixture of the compound prepared in Example 15 (222 mg) and2-aminoethanol (305 mg) was stirred at 100° C. for 1 hour. After coolingthe reaction mixture to room temperature, the deposited crystal waswashed with ethyl acetate. The obtained crystal was recrystallized froma mixed solvent methanol and ethyl acetate to give the compound of thepresent invention (190 mg) having the following physical data.

TLC: Rf 0.23 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.55 (brs, 1H), 8.03 (t, J=5.4 Hz, 1H), 4.66 (t, J=5.4Hz, 1H), 3.41 (s, 2H), 3.38 (m, 2H), 3.11 (m, 2H), 2.42 (brs, 2H), 2.36(brs, 2H), 1.63 (brs, 4H).

EXAMPLE 24(1) TO EXAMPLE 24(48)

By the same procedure as described in Example 24, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 15 or a corresponding ester derivative, anda corresponding derivative instead of 2-aminoethanol, the followingcompounds of the present invention were obtained.

EXAMPLE 24(1)8-(N-(2-aminoethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedihydrochloride

TLC: Rf 0.36 (chloroform:methanol:28% ammonia water=15:5:1);

NMR (DMSO-d₆): δ 12.32 (br-s, 1H), 8.41 (t, J=5.4 Hz, 1H), 8.06 (br-s,3H), 3.49 (s, 2H), 3.30 (m, 2H), 3.20 (m, 2H), 2.86 (m, 2H), 2.38 (t,J=6.0 Hz, 2H), 1.70 (m, 2H).

EXAMPLE 24(2)4-(N-(2-methoxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.53 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.11 (t, J=5.4 Hz, 1H), 3.41 (s, 2H),3.32 (m, 2H), 3.23 (s, 3H), 3.19 (m, 2H), 2.41-2.36 (m, 4H), 1.63 (brs,4H).

EXAMPLE 24(3)4-(N-(2-(N′,N′-diethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.35 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 7.85 (t, J=5.4 Hz, 1H), 3.39 (s, 2H),3.09 (q, J=6.6 Hz, 2H), 2.48-2.32 (m, 10H), 1.67-1.58 (m, 4H), 0.91 (t,J=7.2 Hz, 6H).

EXAMPLE 24(4)4-(N-propylcarbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 8.00 (t, J=6.9 Hz, 1H), 3.39 (s, 2H),2.99 (q, J=6.9 Hz, 2H), 2.46-2.32 (m, 4H), 1.68-1.58 (m, 4H), 1.39(sextet, J=6.9 Hz, 2H), 0.83 (t, J=6.9 Hz, 3H).

EXAMPLE 24(5)4-(N-(4-hydroxybutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.68 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.54 (brs, 1H), 8.00 (t, J=5.6 Hz, 1H), 4.37 (t, J=5.1Hz, 1H), 3.38 (s, 2H), 3.36 (m, 2H), 3.02 (m, 2H), 2.42-2.36 (m, 4H),1.63 (brs, 4H), 1.38 (m, 4H).

EXAMPLE 24(6)4-(N-(furan-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.51 (t, J=5.4 Hz, 1H), 7.56 (m, 1H),6.38 (m, 1H), 6.22 (m, 1H), 4.25 (d, J=5.4 Hz, 2H), 3.44 (s, 2H), 2.37(m, 4H), 1.62 (brs, 4H).

EXAMPLE 24(7)4-(N-(piperidin-4-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.21 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.92 (m, 1H), 8.63 (m, 1H), 8.19 (t,J=5.4 Hz, 1H), 3.42 (s, 2H), 3.21 (m, 2H), 2.97-2.72 (m, 4H), 2.38 (m,4H), 1.76-1.26 (m, 9H).

EXAMPLE 24(8)4-(N-(2,3,4,5-tetrahydrofuran-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.45 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.10 (t, J=5.7 Hz, 1H), 3.85-3.56 (m,3H), 3.42 (s, 2H), 3.18-3.04 (m, 2H), 2.41-2.36 (m, 4H), 1.90-1.42 (m,8H).

EXAMPLE 24(9)4-(1-(N-(2-(piperidin-1-yl)ethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.20 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.60 (brs, 1H), 7.80 (t, J=5.7 Hz, 1H), 3.69 (q, J=6.9Hz, 1H), 3.20-3.05 (m, 2H), 2.48-2.25 (m, 10H), 1.65-1.34 (m, 10H), 1.30(d, J=6.9 Hz, 3H).

EXAMPLE 24(10)4-(N-(2-(pyridin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.53 (brs, 1H), 8.44 (d, J=6.3 Hz, 2H), 8.10 (t, J=5.7Hz, 1H), 7.22 (d, J=6.3 Hz, 2H), 3.35 (m, 4H), 2.84-2.63 (m, 2H),2.34-2.27 (m, 4H), 1.59 (brs, 4H).

EXAMPLE 24(11)4-(N-(2-(pyridin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.36 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.48 (d, J=3.9 Hz, 1H), 8.09 (t, J=5.4Hz, 1H), 7.70 (m, 1H), 7.23 (m, 2H), 3.42 (td, J=6.9, 5.4 Hz, 2H), 3.36(s, 2H), 2.87 (t, J=6.9 Hz, 2H), 2.33 (m, 4H), 1.60 (brs, 4H).

EXAMPLE 24(12)4-(N-(2,2-dimethyl-3-(N′,N′-dimethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.24 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 7.89 (t, J=6.0 Hz, 1H), 3.44 (s, 2H),2.95 (d, J=6.0 Hz, 2H), 2.43 (m, 2H), 2.36 (m, 2H), 2.15 (s, 6H), 2.05(s, 2H), 1.63 (brs, 4H), 0.78 (s, 6H).

EXAMPLE 24(13)4-(N-(2-(N′-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.27 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.57 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.09 (q,J=6.0 Hz, 2H), 2.66 (m, 1H), 2.58-2.48 (m, 2H), 2.45-2.32 (m, 4H),1.68-1.59 (m, 4H), 0.93 (d, J=6.0 Hz, 6H).

EXAMPLE 24(14)4-(N-(2-(N′-ethylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.22 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.53 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.10 (q,J=6.0 Hz, 2H), 2.57-2.45 (m, 4H), 2.45-2.34 (m, 4H), 1.68-1.58 (m, 4H),0.97 (t, J=6.9 Hz, 3H).

EXAMPLE 24(15)4-(N-(3-(N′-methylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.20 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 8.01 (t, J=6.9 Hz, 1H), 3.38 (s, 2H), 3.07 (q, J=6.9Hz, 2H), 2.41 (t, J=6.9 Hz, 2H), 2.45-2.33 (m, 4H), 2.21 (s, 3H),1.70-1.60 (m, 4H), 1.52 (quin, J=6.9 Hz, 2H).

EXAMPLE 24(16)4-(N-(2-(pyridin-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.47 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.40 (m, 2H), 8.10 (t, J=5.7 Hz, 1H),7.61 (m, 1H), 7.30 (m, 1H), 3.36 (s, 2H), 3.31 (m, 2H), 2.73 (t, J=6.9Hz, 2H), 2.31 (m, 4H), 1.60 (brs, 4H).

EXAMPLE 24(17)4-(N-(1-benzylpiperidin-4-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.38 (methanol:methylene chloride=1:10);

NMR (CD₃OD): δ 7.36 (m, 5H), 3.76 (m, 1H), 3.69 (s, 2H), 3.59 (s, 2H),3.01 (m, 2H), 2.56 (brs, 4H), 2.33 (m, 2H), 1.97-1.61 (m, 8H).

Hydrochloride:

TLC: Rf 0.49 (methanol:methylene chloride:saturated aqueousammonia=1:9:0.1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 10.63 (brs, 1H), 8.33 (d, J=7.2 Hz, 1H),7.58 (m, 2H), 7.44 (m, 3H), 4.29-2.92 (m, 9H), 2.38 (m, 4H), 1.94-1.70(m, 4H), 1.62 (brs, 4H).

EXAMPLE 24(18)4-(N-(2-(N′-phenylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.47 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.12 (t, J=5.7 Hz, 1H), 7.05 (dd,J=8.4, 7.2 Hz, 2H), 6.52 (m, 3H), 5.55 (t, J=5.7 Hz, 1H), 3.42 (s, 2H),3.22 (m, 2H), 3.06 (m, 2H), 2.38 (m, 4H), 1.60 (brs, 4H).

Hydrochloride:

TLC: Rf 0.57 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.31 (m, 1H), 7.35-7.04 (m, 5H), 3.44(s, 2H), 3.33-3.23 (m, 4H), 2.38 (m, 4H), 1.62 (brs, 4H).

EXAMPLE 24(19)4-(N-(2-(1-methylpyrrol-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.47 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.13 (t, J=5.7 Hz, 1H), 6.58 (t, J=2.4Hz, 1H), 5.84 (t, J=2.4 Hz, 1H), 5.76 (brs, 1H), 3.49 (s, 3H), 3.39 (s,2H), 3.24 (m, 2H), 2.64 (t, J=7.2 Hz, 2H), 2.37 (m, 4H), 1.63 (brs, 4H).

EXAMPLE 24(20)4-(N-(5-hydroxypentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.29 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.33 (t, J=5.4Hz, 1H), 3.38 (s, 2H), 3.35 (m, 2H), 3.02 (td, J=6.3, 5.4 Hz, 2H), 2.39(m, 4H), 1.63 (brs, 4H), 1.41-1.22 (m, 6H).

EXAMPLE 24(21)4-(N-(2-(N′-benzylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.15 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.55 (brs, 1H), 7.97 (t, J=6.0 Hz, 1H), 7.30-7.17 (m,5H), 3.67 (s, 2H), 3.40 (s, 2H), 3.15 (q, J=6.0 Hz, 2H), 2.56-2.35 (m,6H), 1.61 (brs, 4H).

EXAMPLE 24(22)4-(N-(2-(furan-2-ylmethylthio)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.38 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.56 (t, J=1.5Hz, 1H), 6.37 (dd, J=3.0, 1.5 Hz, 1H), 6.26 (d, J=3.0 Hz, 1H), 3.77 (s,2H), 3.40 (s, 2H), 3.22 (m, 2H), 2.53-2.36 (m, 6H), 1.63 (brs, 4H).

EXAMPLE 24(23)4-(N-(3-(2-methylpiperidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.43 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.00 (t, J=5.7 Hz, 1H), 3.38 (s, 2H),3.03 (m, 2H), 2.73-1.96 (m, 11H), 1.63-1.13 (m, 10H), 0.94 (d, J=6.3 Hz,3H).

EXAMPLE 24(24)4-(N-(3-(N′-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.01 (t, J=5.1 Hz, 1H), 3.38 (s, 2H),3.08 (m, 2H), 2.51-2.25 (m, 7H), 1.77-0.92 (m, 16H).

EXAMPLE 24(25)4-(N-(2-(N′-butylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.66 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 7.95 (t, J=5.4 Hz, 1H), 3.40 (s, 2H),3.11 (m, 2H), 2.55-2.36 (m, 8H), 1.63 (brs, 4H), 1.31 (m, 4H), 0.85 (t,J=6.9 Hz, 3H).

EXAMPLE 24(26)4-(N-(2-(N′-(2-hydroxypropyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.51 (methanol:methylene chloride:saturated aqueousammonia=1:10:0.1);

NMR (DMSO-d₆): δ 7.99 (t, J=5.1 Hz, 1H), 4.44 (brs, 1H), 3.62 (m, 1H),3.40 (s, 2H), 3.11 (m, 2H), 2.57-2.37 (m, 8H), 1.63 (brs, 4H), 1.01 (d,J=6.3 Hz, 3H).

EXAMPLE 24(27)4-(N-(3-(N′-methyl-N′-phenylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.58 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.07 (t, J=5.4 Hz, 1H), 7.14 (t, J=7.5Hz, 2H), 6.61 (m, 3H), 3.41 (s, 2H), 3.29 (m, 2H), 3.08 (m, 2H), 2.83(s, 3H), 2.39 (m, 4H), 1.62 (m, 6H).

EXAMPLE 24(28)4-(N-(3-hydroxypropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.26 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.54 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.41 (t, J=5.4Hz, 1H), 3.40 (m, 2H), 3.39 (s, 2H), 3.09 (m, 2H), 2.39 (m, 4H), 1.63(brs, 4H), 1.58-1.49 (m, 2H).

EXAMPLE 24(29)4-(N-(2-(thiophen-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.48 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.16 (t, J=5.7 Hz, 1H), 7.32 (d, J=5.1Hz, 1H), 6.94 (dd, J=5.1, 3.3 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H), 3.39 (s,2H), 3.30 (m, 2H), 2.92 (t, J=6.9 Hz, 2H), 2.35 (brs, 4H), 1.62 (brs,4H).

EXAMPLE 24(30)4-(N-(2-(1-methylpyrrolidin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.01 (t, J=5.4 Hz, 1H), 3.38 (s, 2H),3.07 (m, 2H), 2.88 (m, 1H), 2.38 (m, 4H), 2.15 (s, 3H), 2.03-1.24 (m,12H).

EXAMPLE 24(31)4-(N-(2-(1-benzylpiperidin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 7.96 (t, J=5.4 Hz, 1H), 7.32-7.19 (m,5H), 3.40 (s, 2H), 3.37 (s, 2H), 3.06 (m, 2H), 2.75 (m, 2H), 2.31 (m,4H), 1.87-1.03 (m, 13H).

Hydrochloride:

TLC: Rf 0.48 (methanol:methylene chloride:saturated aqueousammonia=1:9:0.1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 10.21 (brs, 1H), 8.05 (t, J=5.4 Hz, 1H),7.56 (m, 2H), 7.45 (m, 3H), 4.24 (m, 2H), 3.38-2.78 (m, 8H), 2.37 (m,4H), 1.83-1.31 (m, 11H).

EXAMPLE 24(32)4-(N-(2-(N′-(2-hydroxyethyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.55 (br, 1H), 7.99 (t, J=6.0 Hz, 1H), 4.43 (m, 1H),3.44-3.37 (m, 2H), 3.40 (s, 2H), 3.11 (q, J=6.0 Hz, 2H), 2.59-2.52 (m,4H), 2.45-2.33 (m, 4H), 1.68-1.60 (m, 4H).

EXAMPLE 24(33)4-(N-(3-methylthiopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.05 (t, J=5.4 Hz, 1H), 3.39 (s, 2H),3.11 (m, 2H), 2.44-2.36 (m, 6H), 2.02 (s, 3H), 1.66 (m, 6H).

EXAMPLE 24(34)4-(N-(2-(N′-ethyl-N′-(3-methylphenyl)amino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.63 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.59 (brs, 1H), 8.12 (t, J=5.4 Hz, 1H), 7.00 (dd,J=7.2, 7.2 Hz, 1H), 6.50 (m, 2H), 6.37 (d, J=7.2 Hz, 1H), 3.40 (s, 2H),3.33-3.18 (m, 6H), 2.38 (m, 4H), 2.20 (s, 3H), 1.62 (brs, 4H), 1.04 (t,J=6.9 Hz, 3H).

EXAMPLE 24(35)4-(N-(4,4-dimethoxybutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.34 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.01 (t, J=5.4 Hz, 1H), 4.31 (t, J=5.4Hz, 1H), 3.39 (s, 2H), 3.19 (s, 6H), 3.01 (m, 2H), 2.39 (m, 4H), 1.63(brs, 4H), 1.52-1.34 (m, 4H).

EXAMPLE 24(36)4-(N-(3-(N′,N′-diethylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.34 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 3.38 (s, 2H),3.05 (q, J=5.7 Hz, 2H), 2.44-2.29 (m, 10H), 1.66-1.59 (m, 4H), 1.49(quin, J=5.7 Hz, 2H), 0.91 (t, J=6.9 Hz, 6H).

EXAMPLE 24(37)4-(N-(3-(N′-isopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.18 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.52 (br, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.08 (q,J=6.0 Hz, 2H), 2.62 (sep, J=6.0 Hz, 1H), 2.48-2.32 (m, 6H), 1.68-1.60(m, 4H), 1.49 (quin, J=6.0 Hz, 2H), 0.92 (d, J=6.0 Hz, 6H).

EXAMPLE 24(38)4-(N-(2-(1,3-dioxolan-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.01 (t, J=5.7 Hz, 1H), 4.79 (t, J=4.8Hz, 1H), 3.89-3.71 (m, 4H), 3.38 (s, 2H), 3.13 (m, 2H), 2.38 (m, 4H),1.70 (m, 2H), 1.63 (brs, 4H).

EXAMPLE 24(39)4-(N-(3-(N′-propylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.60 (br, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.08 (q,J=6.6 Hz, 2H), 2.47-2.34 (m, 8H), 1.70-1.60 (m, 4H), 1.50 (quin, J=6.6Hz, 2H), 1.38 (sex, J=6.6 Hz, 2H), 0.83 (t, J=6.6 Hz, 3H).

EXAMPLE 24(40)4-(N-(2-(N′-propylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.31 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.59 (br, 1H), 7.96 (m, 1H), 3.40 (s, 2H), 3.11 (q,J=6.3 Hz, 2H), 2.57-2.47 (m, 2H), 2.45-2.33 (m, 6H), 1.70-1.60 (m, 4H),1.37 (sex, J=7.2 Hz, 2H), 0.84 (t, J=7.2 Hz, 3H).

EXAMPLE 24(41)4-(N-(2-(4-methoxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.47 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.04 (t, J=5.7 Hz, 1H), 7.10 (d, J=8.7Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.70 (s, 3H), 3.36 (s, 2H), 3.24 (m,2H), 2.63 (t, J=7.2 Hz, 2H), 2.33 (m, 4H), 1.60 (brs, 4H).

EXAMPLE 24(42)4-(N-(2-(4-aminophenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.39 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 10.38 (brs, 3H), 8.19 (t, J=5.4 Hz,1H), 7.31 (m, 4H), 3.37 (s, 2H), 3.29 (q, J=6.9 Hz, 2H), 2.73 (t, J=6.9Hz, 2H), 2.35 (brs, 4H), 1.61 (brs, 4H).

EXAMPLE 24(43)8-(N-(2-(N′-phenylamino)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedihydro chloride

TLC: Rf 0.40 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.27 (brs, 1H), 8.36 (m, 1H), 7.31 (t, J=7.8 Hz, 2H),7.10-6.00 (m, 7H), 3.46 (s, 2H), 3.24 (m, 6H), 2.38 (t, J=6.3 Hz, 2H),1.70 (m, 2H).

EXAMPLE 24(44)8-(N-(2-(1-benzylpiperidin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueousammonia=1:10:0.1);

NMR (DMSO-d₆): δ 11.87 (s, 1H), 9.20 (brs, 1H), 8.05 (t, J=5.1 Hz, 1H),7.48 (m, 5H), 6.38 (brs, 1H), 4.27 (m, 2H), 3.33-3.06 (m, 8H), 2.83 (m,2H), 2.33 (m, 2H), 2.30 (s, 3H), 1.87-1.22 (m, 9H).

EXAMPLE 24(45)8-(N-(3-(morpholin-4-yl)propyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.31 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.85 (s, 1H), 8.05 (t, J=5.4 Hz, 1H), 6.41 (s, 1H),3.54 (m, 4H), 3.29 (m, 2H), 3.17 (brs, 2H), 3.06 (q, J=6.6 Hz, 2H), 2.28(m, 8H), 1.69 (m, 2H), 1.53 (m, 2H).

EXAMPLE 24(46)8-(N-(2-(piperidin-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.14 (methanol:methylene chloride:acetic acid=1:4:0.2);

NMR (DMSO-d₆): δ 11.91 (s, 1H), 8.94 (brs, 1H), 8.29 (t, J=5.4 Hz, 1H),6.30 (brs, 1H), 3.50-3.38 (m, 6H), 3.12 (m, 4H), 2.90 (m, 2H), 2.35 (m,2H), 2.32 (s, 3H), 1.98-1.33 (m, 8H).

EXAMPLE 24(47)8-(N-(2-(morpholin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.29 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.85 (s, 1H), 7.99 (t, J=5.4 Hz, 1H), 6.40 (s, 1H),3.53 (m, 4H), 3.34 (s, 2H), 3.16 (m, 4H), 2.30 (m, 8H), 1.70 (m, 2H).

EXAMPLE 24(48)8-(N-(3-(N′-t-butoxycarbonylamino)propyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.35 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 11.84 (s, 1H), 8.02 (t, J=5.4 Hz, 1H), 6.76 (t, J=5.4Hz, 1H), 6.38 (s, 1H), 3.31 (m, 2H), 3.18 (brs, 2H), 2.98 (td, J=6.6,5.4 Hz, 2H), 2.90 (td, J=6.6, 5.4 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69(m, 2H), 1.47 (m, 2H), 1.36 (s, 9H).

EXAMPLE 254-(3-(N-(5-chloropentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

5-chloropentanoyl chloride (171 mg) was added dropwise to a mixedsolution of the compound prepared in Example 1 (241 mg) and potassiumcarbonate (89.8 mg) in tetrahydrofuran (3.00 mL) and water (1.00 mL) inice bath and the mixture was stirred for 30 minutes. Moreover, potassiumcarbonate (45.0 mg) and 5-chloropentanoyl chloride (85.5 mg) was addedthe reaction mixture, which was stirred for 30 minutes. 1N hydrochloricacid was added to the reaction mixture, which was adjusted to pH 2.Water was added thereto and the deposited crystal was collected byfiltration. It was washed with water and hexane sequentially and driedunder reduced pressure to give the compound of the present invention(347 mg) having the following physical data.

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.00 (s, 1H), 7.69 (s, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 3.65 (t,J=6.0 Hz, 2H), 2.56-2.32 (m, 6H), 1.75-1.59 (m, 8H).

EXAMPLE 25(1) TO EXAMPLE 25(13)

By the same procedure as described in Example 25 using a correspondingderivative instead of the compound prepared in Example 1, and acorresponding derivative instead of 5-chloropentanoyl chloride, thefollowing compounds of the present invention were obtained.

EXAMPLE 25(1)4-(3-(N-(5-bromopentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.28 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.00 (s, 1H), 7.69 (t, J=1.2 Hz, 1H),7.59 (dd, J=7.8, 1.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (dd, J=7.8,1.2 Hz, 1H), 3.55 (t, J=6.6 Hz, 2H), 2.48-2.32 (m, 6H), 1.86-1.59 (m,8H).

EXAMPLE 25(2)4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.50 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 8.47-8.28 (br, 1H), 7.69 (bs, 1H), 7.62 (bs, 1H), 7.53(d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 4.35(dd, J=10.5, 2.7 Hz, 1H), 3.85 (dt, J=13.5, 2.7 Hz, 1H), 3.67 (t, J=6.3Hz, 2H), 3.21-3.11 (m, 1H), 3.08-3.02 (m, 1H), 2.94 (dd, J=13.5, 10.5Hz, 1H), 2.86-2.76 (m, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.32-2.16 (m, 3H).

EXAMPLE 25(3)4-(3-(N-acetylamino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.40 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 10.52 (s, 1H), 10.05 (s, 1H), 7.67 (s, 1H), 7.56 (d,J=8.1 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.23 (dd,J=8.7, 4.8 Hz, 1H), 3.56 (m, 1H), 3.08 (m, 1H), 2.89-2.83 (m, 2H), 2.70(m, 1H), 2.32 (m, 1H), 2.04 (s, 3H).

EXAMPLE 25(4)4-(3-(N-acetylamino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.51 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.88 (s, 1H), 10.08 (s, 1H), 7.70 (s, 1H), 7.61 (d,J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.26 (s,1H), 3.61 (m, 2H), 3.15 (m, 2H), 2.05 (s, 3H).

EXAMPLE 25(5)4-(3-(N-acetylamino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.45 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.87 (s, 1H), 10.02 (s, 1H), 7.67 (s, 1H), 7.58 (d,J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 2.39 (m,4H), 2.04 (s, 3H), 1.64 (m, 4H).

EXAMPLE 25(6)4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

NMR (DMSO-d₆): δ 10.89 (s, 1H), 10.12 (s, 1H), 7.71 (t, J=1.5 Hz, 1H),7.62 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.10 (dt, J=7.8, 1.5 Hz, 1H), 6.26(s, 1H), 3.70 (t, J=6.9 Hz, 2H), 3.64-3.58 (m, 2H), 3.18-3.13 (m, 2H),2.35 (t, J=6.9 Hz, 2H), 2.03 (quin, J=6.9 Hz, 2H).

EXAMPLE 25(7)4-(3-(N-(2-chloroacetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.27 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.90 (s, 1H), 10.40 (s, 1H), 7.68 (s, 1H), 7.60 (d,J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 4.25 (s,2H), 2.39 (m, 4H), 1.68 (m, 2H), 1.59 (m, 2H).

EXAMPLE 25(8)4-(3-(N-(3-bromopropanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.20 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.15 (s, 1H), 7.70 (s, 1H), 7.60 (d,J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 3.72 (t,J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H), 2.48-2.34 (m, 4H), 1.70 (m, 2H),1.60 (m, 2H).

EXAMPLE 25(9)8-(3-(N-acetylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneFree Form:

TLC: Rf 0.31 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.11 (s, 1H), 10.06 (s, 1H), 7.70 (m, 1H), 7.61 (m,1H), 7.37 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 5.37 (s, 1H), 3.20-3.06(m, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.04 (s, 3H), 1.82-1.60 (m, 2H).

Methanesulfonate:

TLC: Rf 0.31 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.31 (s, 1H), 10.06 (s, 1H), 7.70 (m, 1H), 7.62 (m,1H), 7.38 (t, J=7.9 Hz, 1H), 7.09 (m, 1H), 3.14 (m, 2H), 2.41 (t, J=6.2Hz, 2H), 2.33 (s, 3H), 2.04 (s, 3H), 1.73 (m, 2H).

EXAMPLE 25(10)4-(3-(N-mesylamino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.56 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 9.86 (brs, 1H), 7.39 (t, J=7.8 Hz, 1H),7.25 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 3.00 (s,3H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.59 (m, 2H).

EXAMPLE 25(11)8-(3-(N-(4-chlorobutanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.41 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.11 (s, 1H), 10.09 (s, 1H), 7.72 (m, 1H), 7.63 (s,1H), 7.38 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 5.74 (s, 1H), 3.69 (t,J=6.3 Hz, 2H), 3.22-3.04 (m, 2H), 2.60-2.32 (m, 4H), 2.12-1.94 (m, 2H),1.82-1.64 (m, 2H).

EXAMPLE 25(12)4-(2-(N-(2-bromoacetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.68 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 8.33 (brt, J=5.1 Hz, 1H), 3.82 (s, 2H),3.44-3.26 (m, 2H), 2.64 (t, J=6.9 Hz, 2H), 2.54-2.28 (m, 4H), 1.78-1.52(m, 4H).

EXAMPLE 25(13)4-(2-(N-(3-bromopropanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.71 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.55 (brs, 1H), 8.07 (brt, J=6.0 Hz, 1H), 3.61 (t,J=6.0 Hz, 2H), 3.44-3.24 (m, 2H), 2.72-2.28 (m, 8H), 1.78-1.54 (m, 4H).

EXAMPLE 264-(3-(N-(5-(N′-methyl-N′-t-butoxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A mixture of the compound prepared in Example 1 (277 mg), triethylamine(223 mg), 5-(N-methyl-N-t-butoxycarbonylamino)pentanoic acid (277 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg),1-hydroxybenzotriazole (184 mg) and dimethylformamide (3.00 mL) wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated. Water was added to the residue, which was extracted withethyl acetate. The extract was washed with 1N hydrochloric acid, water,a saturated aqueous sodium hydrogen carbonate solution and brinesequentially, dried over anhydrous magnesium sulfate and concentrated.The residue was recrystallized from a mixed solvent of ethyl acetate andhexane to give the compound of the present invention (298 mg) having thefollowing physical data.

TLC: Rf 0.49 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 9.97 (s, 1H), 7.69 (s, 1H), 7.58 (d,J=8.1 Hz, 1H), 7.35 (t, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.15 (t,J=6.8 Hz, 2H), 2.74 (s, 3H), 2.48-2.30 (m, 6H), 1.70-1.50 (m, 8H), 1.36(s, 9H).

EXAMPLE 26(1) TO EXAMPLE 26(19)

By the same procedure as described in Example 26, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 1 or a corresponding derivative, and(N-methyl-N-t-butoxycarbonylamino)pentanoic acid or a correspondingderivative, the following compounds of the present invention wereobtained.

EXAMPLE 26(1)4-(3-(N-(5-(N′-methyl-N′-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.29 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 9.98 (s, 1H), 7.70 (s, 1H), 7.58 (d,J=7.8 Hz, 1H), 7.32 (m, 6H), 7.08 (d, J=7.8 Hz, 1H), 5.04 (s, 2H),3.28-2.33 (m, 11H), 1.69-1.51 (m, 8H).

EXAMPLE 26(2)4-(3-(N-(4-chlorobutanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.48 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.07 (s, 1H), 7.69 (s, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 3.69 (t,J=6.3 Hz, 2H), 2.46-1.59 (m, 12H).

EXAMPLE 26(3)4-(3-(N-(5-(N′,N′-dimethylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.30 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (CD₃OD): δ 7.75 (t, J=1.8 Hz, 1H), 7.63 (brd, J=8.1 Hz, 1H), 7.45(t, J=8.1 Hz, 1H), 7.20 (brd, J=8.1 Hz, 1H), 3.16 (m, 2H), 2.89 (s, 6H),2.74 (s, 3H), 2.66-2.50 (m, 6H), 1.81 (m, 8H).

EXAMPLE 26(4)4-(3-(N-(5-(N′-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.79 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 9.97 (s, 1H), 7.69 (s, 1H), 7.59 (d,J=7.8 Hz, 1H), 7.37-7.26 (m, 6H), 7.08 (d, J=7.8 Hz, 1H), 4.99 (s, 2H),3.00 (m, 2H), 2.48-2.28 (m, 6H), 1.69-1.42 (m, 8H).

EXAMPLE 26(5)4-(3-(N-(2-(2-chloroethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 9.81 (s, 1H), 7.73 (s, 1H), 7.67 (d,J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 4.14 (s,2H), 3.81 (s, 4H), 2.48-2.34 (m, 4H), 1.70-1.59 (m, 4H).

EXAMPLE 26(6)4-(3-(N-(5-(N′-methyl-N′-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-one

TLC: Rf 0.28 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 10.34 (s, 1H), 9.98 (s, 1H), 7.68 (s, 1H), 7.56 (d,J=9.0 Hz, 1H), 7.33 (m, 6H), 7.01 (d, J=7.8 Hz, 1H), 5.04 (s, 2H), 3.86(m, 1H), 3.25-1.42 (m, 19H).

EXAMPLE 26(7)4-(3-(5-(N′-methyl-N′-benzyloxycarbonylamino)pentanoyl)aminophenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.24 (methanol:chloroform=1:10);

NMR (DMSO-d₆): δ 10.53 (s, 1H), 10.01 (s, 1H), 7.67 (t, J=1.5 Hz, 1H),7.58 (m, 1H), 7.34 (m, 6H), 7.06 (m, 1H), 5.04 (s, 2H), 4.23 (dd, J=8.6,4.8 Hz, 1H), 3.57 (brd, J=13.8 Hz, 1H), 3.28 (m, 3H), 3.07 (t, J=12.0Hz, 1H), 2.88-2.65 (m, 5H), 2.33 (m, 3H), 1.52 (m, 4H).

EXAMPLE 26(8)4-(3-(N-(5-(N′-methyl-N′-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-one

TLC: Rf 0.54 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.58 (br-s, 1H), 8.21 (br-s, 1H), 7.69 (br-s, 1H), 7.60(m, 1H), 7.40-7.28 (m, 6H), 7.04 (m, 1H), 5.13 (s, 2H), 3.42-3.28 (m,2H), 3.00-2.86 (m, 5H), 2.70-2.64 (m, 2H), 2.46-2.30 (m, 2H), 1.94-1.84(m, 2H), 1.80-1.60 (m, 8H).

EXAMPLE 26(9)4-(3-(N-(4-(N′-methyl-N′-t-butoxycarbonylamino)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.35 (methylene chloride:methanol=10:1).

EXAMPLE 26(10)4-(3-(N-(6-(N′-methyl-N′-t-butoxycarbonylamino)hexanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.35 (methylene chloride:methanol=10:1).

EXAMPLE 26(11)4-(3-(N-(5-(N′-(3-methyl-2-butenyl)-N′-t-butoxycarbonylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.31 (hexane:ethyl acetate=1:3);

NMR (DMSO-d₆): δ 12.87 (s, 1H), 9.95 (s, 1H), 7.68 (m, 1H), 7.58 (m,1H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.07 (m, 1H), 5.10 (m, 1H), 3.72 (d,J=6.6 Hz, 2H), 3.16-3.00 (m, 2H), 2.62-2.40 (m, 2H), 2.40-2.22 (m, 4H),1.78-1.30 (m, 8H), 1.64 (s, 3H), 1.60 (s, 3H), 1.36 (s, 9H).

EXAMPLE 26(12)4-(3-(N-(5-(N′-methyl-N′-benzyloxycarbonylamino)pentanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.63 (chloroform:methanol:water=8:2:0.2);

NMR (CD₃OD): δ 7.74 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz,1H), 7.35-7.20 (m, 5H), 7.14 (d, J=7.8 Hz, 1H), 6.39 (s, 1H), 5.08 (s,2H), 3.73-3.68 (m, 2H), 3.38-3.28 (m, 2H), 3.16-3.10 (m, 2H), 2.91 (brs,3H), 2.44-2.25 (m, 2H), 1.78-1.50 (m, 4H).

EXAMPLE 26(13)4-(3-(N-(2-(N′,N′-dimethylamino)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.27 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.92 (s, 1H), 10.97 (s, 1H), 9.96 (brs, 1H), 7.72 (m,1H), 7.65 (m, 1H), 7.43 (dd, J=7.8, 7.8 Hz, 1H), 7.20 (m, 1H), 4.16 (s,2H), 2.87 (s, 6H), 2.60-2.24 (m, 4H), 1.80-1.50 (m, 4H).

EXAMPLE 26(14)4-(3-(N-(1-t-butoxycarbonylazetidin-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.27 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.13 (s, 1H), 7.71 (m, 1H), 7.60 (m,1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.12 (m, 1H), 4.08-3.84 (m, 4H), 3.46(m, 1H), 2.54-2.28 (m, 4H), 1.78-1.52 (m, 4H), 1.38 (s, 9H).

EXAMPLE 26(15)4-(3-(N-(1-t-butoxycarbonylpyrrolidin-2-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.07 (s, 1H), 7.71 (s, 1H), 7.62 (d,J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.17 (m,1H), 3.38-2.34 (m, 8H), 1.98-1.60 (m, 6H), 1.38 (s, 9H×⅓), 1.26 (s,9H×⅔).

EXAMPLE 26(16)4-(2-(N-(2-(N′-t-butoxycarbonylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.31 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.54 (s, 1H), 7.82 (brt, 1H), 6.91 (brt, 1H), 3.47 (d,J=6.3 Hz, 2H), 3.40-3.26 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.56-2.30 (m,4H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).

EXAMPLE 26(17)4-(2-(N-(3-(N′-t-butoxycarbonylamino)propanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.54 (s, 1H), 7.92 (t, J=6.0 Hz, 1H), 6.72 (brt, 1H),3.42-3.18 (m, 2H), 3.16-3.02 (m, 2H), 2.68-2.28 (m, 6H), 2.18 (t, J=7.2Hz, 2H), 1.78-1.52 (m, 4H), 1.36 (s, 9H).

EXAMPLE 26(18)4-(2-(N-(2-(N′,N′-dimethylamino)acetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.62 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.54 (brs, 1H), 7.80 (t, J=5.7 Hz, 1H), 3.44-3.24 (m,2H), 2.80 (s, 2H), 2.64 (t, J=7.2 Hz, 2H), 2.54-2.26 (m, 4H), 2.16 (s,6H), 1.76-1.52 (m, 4H).

EXAMPLE 26(19)4-(2-(N-(4-(N′-t-butoxycarbonylamino)butanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.67 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.53 (s, 1H), 7.85 (t, J=5.4 Hz, 1H), 6.78 (t, J=5.7Hz, 1H), 3.40-3.20 (m, 2H), 2.94-2.80 (m, 2H), 2.60 (t, J=7.2 Hz, 2H),2.56-2.28 (m, 4H), 2.01 (t, J=7.2 Hz, 2H), 1.78-1.46 (m, 6H), 1.36 (s,9H).

EXAMPLE 274-(2-(N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The compound prepared in Reference example 13 (40 mg), sodium iodide(8.4 mg) and benzylamine (0.21 mL) were stirred at room temperature for10 hours. Methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture, which wasseparated. The organic layer was dried over anhydrous magnesium sulfateand concentrated. The residue was purified by column chromatography onsilica gel (chloroform:methanol=50:1) to give the compound of thepresent invention (18 mg) having the following physical data.

TLC: Rf 0.29 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.46 (s, 1H), 7.40-7.15 (m, 5H), 3.69 (s, 2H),2.80-2.60 (m, 4H), 2.50-2.30 (m, 4H), 1.63 (brs, 4H).

EXAMPLE 27(1) TO EXAMPLE 27(80)

By the same procedure as described in Example 27, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Reference example 13 or a corresponding derivative,and a corresponding derivative instead of benzylamine, the followingcompounds of the present invention were obtained.

EXAMPLE 27(1)4-(2-(morpholin-4-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one FreeForm:

TLC: Rf 0.38 (chloroform:methanol:acetic acid=90:10:1);

NMR (CD₃OD): δ 3.74-3.66 (m, 4H), 2.84-2.77 (m, 2H), 2.75-2.66 (m, 2H),2.64-2.48 (m, 8H), 1.88-1.72 (m, 4H).

Hydrochloride:

TLC: Rf 0.24 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.68 (s, 1H), 10.85 (brs, 1H), 4.02-3.92 (m, 2H),3.82-3.70 (m, 2H), 3.54-3.44 (m, 2H), 3.44-3.32 (m, 2H), 3.15-3.05 (m,2H), 3.05-2.96 (m, 2H), 2.53-2.33 (m, 4H), 1.76-1.58 (m, 4H).

EXAMPLE 27(2)4-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.12 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 3.78-3.66 (m, 2H), 3.63 (t, J=8.1 Hz, 2H), 3.26-3.10 (m,2H), 3.06 (t, J=8.1 Hz, 2H), 2.62-2.48 (m, 4H), 2.26-1.96 (m, 4H),1.90-1.72 (m, 4H).

EXAMPLE 27(3)4-(2-(4-methylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.68 (s, 1H), 11.80 (brs, 2H), 4.00-3.20 (m, 10H),3.10-2.95 (m, 2H), 2.80 (s, 3H), 2.50-2.30 (m, 4H), 1.75-1.55 (m, 4H).

EXAMPLE 27(4)4-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 10.45 (brs, 1H), 3.52-3.42 (m, 2H),3.34-3.22 (m, 2H), 3.06-2.96 (m, 2H), 2.96-2.80 (m, 2H), 2.54-2.32 (m,4H), 1.84-1.56 (m, 9H), 1.46-1.26 (m, 1H).

EXAMPLE 27(5)4-(2-(N-cyclohexylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.65 (s, 1H), 8.85 (brs, 2H), 3.26-3.10 (m, 2H),3.10-2.96 (m, 1H), 2.90 (t, J=7.2 Hz, 2H), 2.50-2.36 (m, 4H), 2.06-1.98(m, 2H), 1.80-1.54 (m, 7H), 1.40-1.00 (m, 5H).

EXAMPLE 27(6)4-(2-(azepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.28 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 10.55 (s, 1H), 3.46-3.28 (m, 4H),3.20-3.06 (m, 2H), 3.06-2.98 (m, 2H), 2.56-2.46 (m, 2H), 2.44-2.34 (m,2H), 1.90-1.50 (m, 12H).

EXAMPLE 27(7)4-(2-(4-t-butoxycarbonylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.29 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.51 (s, 1H), 3.32-3.24 (m, 6H), 2.70-2.60 (m, 2H),2.60-2.50 (m, 2H), 2.40-2.30 (m, 6H), 1.72-1.56 (m, 4H), 1.37 (s, 9H).

EXAMPLE 27(8)4-(2-(thiomorpholin-4-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.40 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.67 (s, 1H), 10.90 (brs, 1H), 3.84-3.70 (m, 2H),3.44-3.30 (m, 2H), 3.24-3.10 (m, 4H), 3.08-2.98 (m, 2H), 2.90-2.76 (m,2H), 2.52-2.44 (m, 2H), 2.42-2.34 (m, 2H), 1.76-1.58 (m, 4H).

EXAMPLE 27(9)4-(2-(N-(2-propynyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.28 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 9.70-9.45 (m, 2H), 3.98-3.88 (m, 2H),3.70 (t, J=2.4 Hz, 1H), 3.30-3.18 (m, 2H), 2.91 (t, J=7.8 Hz, 2H),2.48-2.32 (m, 4H), 1.76-1.58 (m, 4H).

EXAMPLE 27(10)4-(2-(4-ethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.19 (chloroform:methanol=5:1);

NMR (CD₃OD): δ 2.84-2.76 (m, 2H), 2.75-2.67 (m, 2H), 2.67-2.47 (m, 12H),2.44 (q, J=7.5H, 2H), 1.79 (m, 4H), 1.10 (t, J=7.5 Hz, 3H).

EXAMPLE 27(11)4-(2-(N-cyclohexylmethylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.49 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 8.86 (brs, 2H), 3.26-3.08 (m, 2H),3.02-2.88 (m, 2H), 2.86-2.70 (m, 2H), 2.58-2.30 (m, 4H), 1.88-1.50 (m,10H), 1.32-0.82 (m, 5H).

EXAMPLE 27(12)4-(2-(azocan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (chloroform:methanol=5:1);

NMR (CD₃OD): δ 3.61 (t, J=6.6 Hz, 2H), 3.58-3.30 (m, 4H), 3.08 (t, J=6.6Hz, 2H), 2.62-2.50 (m, 4H), 2.12-1.60 (m, 14H).

EXAMPLE 27(13)4-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.29 (chloroform:methanol:saturated aqueous ammonia=5:1:0.1);

NMR (CD₃OD): δ 3.26 (m, 4H), 3.08-3.01 (m, 4H), 2.96 (t, J=6.0 Hz, 2H),2.84 (m, 2H), 2.81 (s, 3H), 2.60 (m, 2H), 2.52 (m, 2H), 2.03 (m, 2H),1.80 (m, 4H).

EXAMPLE 27(14)4-(2-(N-(2-(N′-t-butoxycarbonylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.47 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.52 (brs, 1H), 6.73 (brt, 1H), 3.34 (br, 1H),3.06-2.94 (m, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.70-2.54 (m, 4H), 2.54-2.28(m, 4H), 1.76-1.54 (m, 4H), 1.36 (s, 9H).

EXAMPLE 27(15)4-(2-(4-phenylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.50 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.23 (dd, J=7.5, 7.5 Hz, 2H), 6.97 (d, J=7.5 Hz, 2H),6.83 (dd, J=7.5, 7.5 Hz, 1H), 3.20 (m, 4H), 2.90-2.70 (m, 8H), 2.62 (m,2H), 2.52 (m, 2H), 1.80 (m, 4H).

EXAMPLE 27(16)4-(2-(4-(2-chlorophenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (chloroform:methanol=9:1);

NMR (CDCl₃): δ 10.61 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.8,7.8 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.98 (dd, J=7.8, 7.8 Hz, 1H), 3.11(m, 4H), 2.78 (s, 4H), 2.74 (m, 4H), 2.59 (m, 2H), 2.53 (m, 2H), 1.78(m, 4H).

EXAMPLE 27(17)4-(2-(4-benzylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.43 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.36-7.22 (m, 5H), 3.54 (s, 2H), 2.84-2.64 (m, 4H),2.64-2.45 (m, 12H), 1.86-1.72 (m, 4H).

EXAMPLE 27(18)4-(2-(N-(4-trifluoromethylbenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.33 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.63 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.90 (s,2H), 2.96 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.77(m, 4H).

EXAMPLE 27(19)4-(2-(N-methyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.32 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.28 (m, 5H), 3.56 (s, 2H), 2.83-2.65 (m, 4H), 2.49 (m,4H), 2.31 (s, 3H), 1.73 (m, 4H).

Methanesulfonate:

TLC: Rf 0.44 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.69 (s, 1H), 9.42 (m, 1H), 7.49 (m, 5H), 4.48 (m,1H), 4.31 (m, 1H), 3.50-3.25 (m, 2H), 2.98 (m, 2H), 2.75 (m, 3H), 2.38(m, 4H), 2.29 (s, 3H), 1.68 (m, 4H).

EXAMPLE 27(20)4-(2-(N-(2-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (methanol:methylene chloride=1:10);

NMR (CD₃OD): δ 7.37 (m, 5H), 3.52 (t, J=6.8 Hz, 2H), 3.38 (m, 2H), 3.07(m, 4H), 2.60 (m, 4H), 1.85 (m, 4H).

EXAMPLE 27(21)4-(2-(N-(4-trifluoromethoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.44 (d, J=7.5 Hz, 2H), 7.23 (d, J=7.5 Hz, 2H), 3.82 (s,2H), 2.93 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H), 2.59-2.49 (m, 4H),1.77 (m, 4H).

EXAMPLE 27(22)4-(2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.55 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 8.08 (m, 1H), 7.56 (m, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.68(dd, J=6.3, 4.8 Hz, 1H), 3.54 (t, J=5.1 Hz, 4H), 2.90-2.74 (m, 4H), 2.68(t, J=5.1 Hz, 4H), 2.62 (m, 2H), 2.52 (m, 2H), 1.79 (m, 4H).

EXAMPLE 27(23)4-(2-(N-(2-(N′-phenylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.26 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.18-7.08 (m, 2H), 6.74-6.64 (m, 3H), 3.48-3.36 (m, 4H),3.22 (t, J=6.0 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.51 (m, 4H), 1.78 (m,4H).

EXAMPLE 27(24)4-(2-(4-acetylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.21 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 3.62-3.52 (m, 4H), 2.85-2.70 (m, 4H), 2.64-2.48 (m, 8H),2.09 (s, 3H), 1.79 (m, 4H).

EXAMPLE 27(25)4-(2-(N-(naphthalen-1-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.45 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.49 (brs, 1H), 8.15 (m, 1H), 7.89 (m, 1H), 7.79 (d,J=7.2 Hz, 1H), 7.53-7.40 (m, 4H), 4.15 (s, 2H), 2.87 (t, J=7.2 Hz, 2H),2.69 (t, J=7.2 Hz, 2H), 2.35 (m, 4H), 1.62 (brs, 4H).

EXAMPLE 27(26)4-(2-(N-ethyl-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 7.30-7.20 (m, 5H), 3.60 (s, 2H), 2.72 (s, 4H), 2.62 (q,J=7.2 Hz, 2H), 2.48 (m, 2H), 2.40 (m, 2H), 1.70 (m, 4H), 1.10 (t, J=7.2Hz, 3H).

EXAMPLE 27(27)4-(2-(N-(1-benzylpiperidin-4-yl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.17 (methylene chloride:methanol:water=9:1:0.1);

NMR (CD₃OD): δ 7.43-7.23 (m, 5H), 3.60 (s, 2H), 3.41 (t, J=6.6 Hz, 2H),3.14 (m, 1H), 3.06-2.98 (m, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.60-2.50 (m,4H), 2.22-2.06 (m, 4H), 1.86-1.60 (m, 6H).

EXAMPLE 27(28)4-(2-(N-(2-hydroxyethyl)-N-benzylamino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.19 (m, 5H), 3.65 (t, J=8.7 Hz, 2H), 3.61 (s, 2H),2.78-2.67 (m, 6H), 2.43 (m, 2H), 2.30 (m, 2H), 1.64 (m, 4H).

EXAMPLE 27(29)4-(2-(4-cyclohexylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.55 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 3.30-2.70 (m, 13H), 2.59 (m, 2H), 2.51 (m, 2H), 2.05 (m,2H), 1.91 (m, 2H), 1.86-1.65 (m, 6H), 1.44-1.20 (m, 4H).

EXAMPLE 27(30)4-(2-(N-(4-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.50 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 7.41 (m, 2H), 7.10 (dd, J=8.7, 8.7 Hz, 2H), 3.94 (s, 2H),3.10 (t, J=6.9 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.78 (m,4H).

Hydrochloride:

TLC: Rf 0.43 (methylene chloride:methanol=4:1);

NMR (DMSO-d₆): δ 12.68 (s, 1H), 9.00 (s, 2H), 7.57 (m, 2H), 7.29 (m,2H), 4.20 (m, 2H), 3.21 (m, 2H), 2.90 (m, 2H), 2.58-2.38 (m, 4H), 1.67(m, 4H).

EXAMPLE 27(31)4-(2-(N-(4-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.39 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.3);

NMR (CD₃OD): δ 7.40 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.15 (s,2H), 3.81 (s, 3H), 3.37 (t, J=6.9 Hz, 2H), 2.95 (t, J=6.9 Hz, 2H), 2.53(m, 4H), 1.78 (m, 4H).

EXAMPLE 27(32)4-(2-(N-(1-phenylethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.38 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.50 (m, 5H), 4.48 (q, J=6.9 Hz, 1H), 3.29 (m, 2H), 2.92(t, J=6.6 Hz, 2H), 2.51 (m, 4H), 1.78 (m, 4H), 1.70 (d, J=6.9 Hz, 3H).

EXAMPLE 27(33)4-(2-(N-(3-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.39 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.48-7.06 (m, 4H), 4.06 (s, 2H), 3.20 (t, J=6.9 Hz, 2H),2.90 (t, J=6.9 Hz, 2H), 2.53 (m, 4H), 1.77 (m, 4H).

EXAMPLE 27(34)4-(2-(4-diphenylmethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.48 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.48-7.40 (m, 4H), 7.32-7.13 (m, 6H), 4.25 (s, 1H), 3.16(t, J=5.1 Hz, 2H), 2.81-2.40 (m, 14H), 1.78 (m, 4H).

EXAMPLE 27(35)4-(2-(N-(3-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.32 (dd, J=8.1, 8.1 Hz, 1H), 7.02-6.90 (m, 3H), 4.05 (s,2H), 3.81 (s, 3H), 3.24 (t, J=6.9 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.51(m, 4H), 1.77 (m, 4H).

EXAMPLE 27(36)8-(2-(piperidin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onehydrochloride

TLC: Rf 0.26 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 11.94 (s, 1H), 9.31 (brs, 1H), 6.39 (brs, 1H),3.60-3.10 (m, 6H), 3.06-2.74 (m, 4H), 2.34 (t, J=6.6 Hz, 2H), 1.94-1.50(m, 7H), 1.38 (m, 1H).

EXAMPLE 27(37)4-(2-(N-(2-phenoxyethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.62 (methylene chloride:methanol:water=4:1:0.2);

NMR (CD₃OD): δ 7.26 (dd, J=8.1, 8.1 Hz, 2H), 6.98-6.88 (m, 3H), 4.11 (t,J=5.1 Hz, 2H), 3.14-3.05 (m, 4H), 2.84 (t, J=6.6 Hz, 2H), 2.60-2.50 (m,4H), 1.78 (m, 4H).

EXAMPLE 27(38)4-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.67 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.3);

NMR (CD₃OD): δ 7.34 (m, 5H), 5.11 (s, 2H), 3.54 (m, 4H), 2.82-2.70 (m,8H), 2.60 (m, 2H), 2.52 (m, 2H), 1.90-1.72 (m, 6H).

Methanesulfonate:

TLC: Rf 0.64 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.7 (s, 1H), 9.35 (s, 1H), 7.40-7.30 (m, 5H), 5.11 (s,2H), 3.89 (m, 1H), 3.72-3.40 (m, 7H), 3.35-3.16 (m, 2H), 2.95 (t, J=7.2Hz, 2H), 2.65-2.50 (m, 4H), 2.30 (s, 3H), 1.85 (m, 2H), 1.67 (m, 4H).

EXAMPLE 27(39)4-(2-(4-cyclopentylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.14 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 4.00-3.40 (m, 11H), 3.12 (t, J=7.5 Hz, 2H), 2.62-2.50 (m,4H), 2.22-2.15 (m, 2H), 1.92-1.68 (m, 10H).

EXAMPLE 27(40)4-(2-(4-butylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.16 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 4.10-3.45 (m, 8H), 3.74 (t, J=7.2 Hz, 2H), 3.30 (m, 2H),3.16 (t, J=7.2 Hz, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 1.90-1.75 (m, 6H),1.45 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).

EXAMPLE 27(41)8-(2-(4-cyclohexylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.36 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.17 (s, 1H), 11.85 (brs, 1H), 5.09 (br, 3H),3.98-3.08 (m, 11H), 2.96 (m, 2H), 2.36 (t, J=6.0 Hz, 2H), 2.10 (m, 2H),1.94-0.98 (m, 12H).

EXAMPLE 27(42)4-(2-(N-(4-chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.75 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 9.39 (brs, 2H), 7.59 (d, J=8.4 Hz, 2H),7.51 (d, J=8.4 Hz, 2H), 4.19 (m, 2H), 3.18 (m, 2H), 2.94 (t, J=7.5 Hz,2H), 2.40 (m, 4H), 1.66 (m, 4H).

EXAMPLE 27(43)4-(2-(4-hexylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.68 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.04-3.45 (m, 8H), 3.71 (t, J=7.2 Hz, 2H), 3.26 (m, 2H),3.15 (t, J=7.2 Hz, 2H), 2.59 (m, 2H), 2.53 (m, 2H), 1.80 (m, 6H), 1.39(m, 6H), 0.93 (t, J=6.9 Hz, 3H).

EXAMPLE 27(44)4-(2-(4-isopropylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.25 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.12-3.58 (m, 11H), 3.18 (t, J=6.9 Hz, 2H), 2.60 (m, 2H),2.53 (m, 2H), 1.80 (m, 4H), 1.44 (d, J=6.9 Hz, 6H).

EXAMPLE 27(45)4-(2-(N-(2-fluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.65 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 7.61-7.50 (m, 2H), 7.32-7.20 (m, 2H), 4.39 (s, 2H), 3.51(t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.52 (m, 4H), 1.79 (m, 4H).

EXAMPLE 27(46)4-(2-(N-(3-methoxypropyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.42 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 3.55 (t, J=6.6 Hz, 2H), 3.45 (t, J=6.9 Hz, 2H), 3.35 (s,3H), 3.21 (t, J=6.9 Hz, 2H), 2.99 (t, J=6.6 Hz, 2H), 2.54 (m, 4H), 1.97(m, 2H), 1.79 (m, 4H).

EXAMPLE 27(47)8-(2-(N-(4-fluorobenzyl)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedihydrochloride

TLC: Rf 0.30 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.41 (brs, 1H), 9.60 (brs, 2H), 7.65 (dd, J=8.4, 5.7Hz, 2H), 7.27 (dd, J=8.4, 8.4 Hz, 2H), 6.00 (brs, 2H), 4.16 (m, 2H),3.34-3.06 (m, 4H), 2.95 (t, J=7.2 Hz, 2H), 2.39 (t, J=6.0 Hz, 2H), 1.71(m, 2H).

EXAMPLE 27(48)4-(2-(N-(furan-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.32 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 9.33 (brs, 2H), 7.78 (d, J=1.5 Hz, 1H),6.65 (d, J=3.3 Hz, 1H), 6.53 (dd, J=3.3, 1.5 Hz, 1H), 4.27 (m, 2H), 3.18(m, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).

EXAMPLE 27(49)4-(2-(N-(4-methylbenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.16 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.66 (s, 1H), 9.23 (brs, 2H), 7.43 (d, J=7.8 Hz, 2H),7.24 (d, J=7.8 Hz, 2H), 4.13 (m, 2H), 3.16 (m, 2H), 2.92 (t, J=7.2 Hz,2H), 2.40 (m, 4H), 2.31 (s, 3H), 1.66 (m, 4H).

EXAMPLE 27(50)4-(2-(N-(2-methoxybenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 7.50-7.42 (m, 2H), 7.15-7.00 (m, 2H), 4.29 (s, 2H), 3.92(s, 3H), 3.48 (t, J=6.6 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.53 (m, 4H),1.78 (m, 4H).

EXAMPLE 27(51)4-(2-(N-(3-methylthiopropyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.069 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 3.47 (t, J=6.6 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 3.00 (t,J=6.6 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H), 2.63-2.50 (m, 4H), 2.12 (s, 3H),2.01 (m, 2H), 1.90-1.75 (m, 4H).

EXAMPLE 27(52)4-(2-(N-(pyridin-4-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.39 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 8.53 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 4.06 (s,2H), 3.15 (t, J=6.9 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.60-2.45 (m, 4H),1.88-1.72 (m, 4H).

EXAMPLE 27(53)8-(2-(4-ethylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.26 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.24 (s, 1H), 11.73 (brs, 1H), 5.59 (br, 3H),4.00-3.06 (m, 14H), 2.97 (t, J=8.1 Hz, 2H), 2.37 (t, J=6.0 Hz, 2H), 1.73(m, 2H), 1.26 (t, J=6.9 Hz, 3H).

EXAMPLE 27(54)4-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.60 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.10-7.00 (m, 4H), 3.82-3.72 (m, 4H), 3.67 (t, J=7.2 Hz,2H), 3.42-3.30 (m, 4H), 3.15 (t, J=7.2 Hz, 2H), 2.65-2.50 (m, 4H), 1.82(m, 4H).

EXAMPLE 27(55)4-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onetrihydrochloride

TLC: Rf 0.14 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 8.28 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 4.50 (m,2H), 3.95-3.30 (m, 6H), 3.71 (t, J=6.9 Hz, 2H), 3.18 (t, J=6.9 Hz, 2H),2.62 (m, 2H), 2.53 (m, 2H), 1.81 (m, 4H).

EXAMPLE 27(56)8-(2-(4-cyclopentylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.45 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.23 (s, 1H), 12.22 (brs, 1H), 4.66 (br, 3H),4.00-3.30 (m, 11H), 3.23 (m, 2H), 2.98 (m, 2H), 2.37 (t, J=6.0 Hz, 2H),2.00 (m, 2H), 1.92-1.40 (m, 8H).

EXAMPLE 27(57)8-(2-(4-isopropylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.26 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.18 (s, 1H), 11.86 (brs, 1H), 4.55 (br, 3H),3.98-3.30 (m, 11H), 3.22 (m, 2H), 2.97 (m, 2H), 2.37 (t, J=6.3 Hz, 2H),1.72 (m, 2H), 1.30 (d, J=6.3 Hz, 6H).

EXAMPLE 27(58)4-(2-(N-(thiophen-2-ylmethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.32 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.65 (s, 1H), 9.59 (brs, 2H), 7.62 (d, J=5.1 Hz, 1H),7.37 (d, J=2.7 Hz, 1H), 7.09 (dd, J=5.1, 2.7 Hz, 1H), 4.41 (s, 2H), 3.18(m, 2H), 2.96 (t, J=7.8 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H).

EXAMPLE 27(59)4-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.72 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.15-6.90 (m, 4H), 3.87 (s, 3H), 3.82-3.05 (m, 8H), 3.67(t, J=6.9 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.62-2.50 (m, 4H), 1.80 (m,4H).

EXAMPLE 27(60)4-(2-(N-methyl-N-(2-(N′,N′-dimethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.5);

NMR (CD₃OD): δ 3.16 (t, J=6.3 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.94-2.83(m, 4H), 2.78 (s, 6H) 2.61 (m, 2H), 2.52 (m, 2H), 2.48 (s, 3H), 1.80 (m,4H).

EXAMPLE 27(61)4-(2-(4-(3-methoxyphenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.54 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.20 (dd, J=8.4, 8.4 Hz, 1H), 6.66-6.52 (m, 3H),3.90-3.08 (m, 8H), 3.77 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2Hz, 2H), 2.61 (m, 2H), 2.54 (m, 2H), 1.81 (m, 4H).

EXAMPLE 27(62)4-(2-(4-((2E)-3-phenyl-2-propenyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.53 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.52 (m, 2H), 7.42-7.32 (m, 3H), 6.96 (d, J=16.2 Hz, 1H),6.36 (dt, J=16.2, 7.2 Hz, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.90-3.45 (m,10H), 3.13 (t, J=7.2 Hz, 2H), 2.59 (m, 2H), 2.53 (m, 2H), 1.79 (m, 4H).

EXAMPLE 27(63)4-(2-(4-(1-methylpropyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.13 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 4.15-3.40 (m, 11H), 3.15 (t, J=6.9 Hz, 2H), 2.60 (m, 2H),2.53 (m, 2H), 2.02-1.58 (m, 6H), 1.41 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.5Hz, 3H).

EXAMPLE 27(64)4-(2-(4-(furan-2-ylcarbonyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.42 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.73 (dd, J=1.8, 0.9 Hz, 1H), 7.17 (dd, J=2.4, 0.9 Hz,1H), 6.63 (dd, J=2.4, 1.8 Hz, 1H), 4.80-4.65 (m, 2H), 3.90-3.25 (m, 6H),3.66 (t, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 2.60 (m, 2H), 2.53 (m,2H), 1.80 (m, 4H).

EXAMPLE 27(65)4-(2-(N-(3-chlorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.38 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.60 (s, 1H), 7.47 (s, 3H), 4.31 (s, 2H), 3.49 (t, J=6.9Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.72 (s, 3H), 2.54 (m, 4H), 1.79 (m,4H).

EXAMPLE 27(66)8-(2-(N-benzylamino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.42 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 7.58-7.45 (m, 5H), 4.28 (s, 2H), 3.47 (t, J=6.6 Hz, 2H),3.34 (m, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.52 (t, J=6.6 Hz, 2H), 1.86 (m,2H).

EXAMPLE 27(67)8-(2-(N-(2-(N′-phenylamino)ethyl)amino)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.23 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 7.15 (m, 2H), 6.69 (m, 3H), 3.50 (m, 4H), 3.32 (m, 4H),2.89 (t, J=6.6 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H), 1.84 (m, 2H).

EXAMPLE 27(68)8-(2-(4-hexylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.51 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.10-3.55 (m, 10H), 3.47 (t, J=5.7 Hz, 2H), 3.30 (m, 2H),3.18 (t, J=7.2 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 1.92 (m, 2H), 1.81 (m,2H), 1.39 (m, 6H), 0.93 (m, 3H).

EXAMPLE 27(69)4-(2-(N-(2,4-difluorobenzyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.15 (methanol:methylene chloride=1:10).

EXAMPLE 27(70)4-(2-(4-(2-methylpropyl)piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.63 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.05-3.50 (m, 8H), 3.78 (t, J=7.2 Hz, 2H), 3.24-3.15 (m,4H), 2.60 (m, 2H), 2.53 (m, 2H), 2.20 (m, 1H), 1.80 (m, 4H), 1.10 (d,J=6.6 Hz, 6H).

EXAMPLE 27(71)8-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.69 (methylene chloride:methanol=9:1);

NMR (CD₃OD): δ 7.12-7.00 (m, 4H), 3.85-3.70 (m, 6H), 3.51 (t, J=5.7 Hz,2H), 3.50-3.18 (m, 6H), 2.67 (t, J=6.3 Hz, 2H), 1.95 (m, 2H).

EXAMPLE 27(72)8-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.12 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 8.15 (d, J=7.8 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 3.90-3.75(m, 4H), 3.35 (m, 2H), 3.05-2.78 (m, 8H), 2.69 (s, 3H), 2.52 (t, J=6.3Hz, 2H), 1.86 (m, 2H).

EXAMPLE 27(73)8-(2-(4-(4-methoxyphenyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.65 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.0 (s, 1H), 9.53 (brs, 1H), 6.97 (d, J=9.0 Hz, 2H),6.85 (d, J=9.0 Hz, 2H), 6.42 (s, 1H), 3.80-3.60 (m, 4H), 3.69 (s, 3H),3.50 (m, 2H), 3.30-3.18 (m, 4H), 2.98-2.80 (m, 4H), 2.35 (m, 2H), 2.32(s, 3H), 1.73 (m, 2H).

EXAMPLE 27(74)4-(2-(N-methyl-N-(3-(N′,N′-dimethylamino)propyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.5%);

NMR (CD₃OD): δ 2.77 (m, 4H), 2.64-2.45 (m, 6H), 2.36 (m, 2H), 2.33 (s,3H), 2.26 (s, 6H), 1.85-1.65 (m, 6H).

EXAMPLE 27(75)4-(2-(N-(2-(N′,N′-diethylamino)ethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.13 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.5%);

NMR (CD₃OD): δ 3.38 (t, J=6.6H, 2H), 3.24 (m, 2H), 3.10 (m, 2H),3.05-2.92 (m, 6H), 2.62-2.48 (m, 4H), 1.80 (m, 4H), 1.21 (t, J=7.2H,6H).

EXAMPLE 27(76)8-(2-(morpholin-4-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneFree Form:

TLC: Rf 0.60 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.73 (s, 1H), 6.58 (s, 1H), 3.58-3.55 (m, 4H), 3.17(m, 2H), 2.58 (m, 4H), 2.41 (m, 4H), 2.32 (t, J=6.0 Hz, 2H), 1.71-1.67(m, 2H).

Methanesulfonate:

TLC: Rf 0.52 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.96 (s, 1H), 9.65 (brs, 1H), 6.36 (s, 1H), 4.01 (m,2H), 3.65 (t, J=11.7 Hz, 2H), 3.45 (m, 4H), 3.16 (m, 4H), 2.83 (t, J=7.8Hz, 2H), 2.35 (m, 2H), 2.31 (s, 3H), 1.72 (m, 2H).

EXAMPLE 27(77)8-(2-(4-methyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.41 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.1);

NMR (DMSO-d₆): δ 11.85 (s, 1H), 10.28 (brs, 1H), 6.41 (s, 1H), 3.32-2.78(m, 16H), 2.42-2.20 (m, 6H), 2.12 (m, 2H), 1.71 (m, 2H).

EXAMPLE 27(78)4-(2-(4-cyclohexylmethylpiperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.52 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.10-3.50 (m, 8H), 3.76 (t, J=6.9H, 2H), 3.20-3.12 (m,4H), 2.65-2.48 (m, 4H), 1.98-1.65 (m, 12H), 1.48-1.00 (m, 3H).

EXAMPLE 27(79)8-(2-(4-butylpiperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.28 (methylene chloride:methanol=4:1);

NMR (CD₃OD): δ 4.15-3.60 (m, 8H), 3.80 (t, J=7.2 Hz, 2H), 3.48 (t, J=5.7Hz, 2H), 3.28 (m, 2H), 3.19 (t, J=7.2 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H),1.94 (m, 2H), 1.80 (m, 2H), 1.45 (m, 2H), 1.01 (t, J=7.2 Hz, 3H).

EXAMPLE 27(80)4-(5-(morpholin-4-yl)pentyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.43 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.48 (s, 1H), 3.54 (t, J=7.5 Hz, 4H), 2.54-2.43 (m,4H), 2.40-2.28 (m, 6H), 2.22 (t, J=7.5 Hz, 2H), 1.74-1.60 (m, 4H),1.64-1.48 (m, 2H), 1.50-1.37 (m, 2H), 1.40-1.26 (m, 2H).

EXAMPLE 284-(3-(N-(5-(morpholin-4-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

A mixture of the compound prepared in Example 25(1) (115 mg) andmorpholine (0.5 mL) was refluxed for 3 hours. The reaction mixture wasconcentrated. Water was added to the residue, which was extracted withethyl acetate. The extract was washed with a saturated aqueous sodiumhydrogen carbonate solution and brine sequentially, dried over anhydrousmagnesium sulfate and concentrated. The residue was recrystallized froma mixed solvent of isopropanol and hexane. A solution of the obtainedsolid (56.2 mg) and methanesulfonic acid (13.2 mg) in methanol (3.0 mL)was stirred at room temperature for 1 hour. The reaction mixture wasconcentrated to give the compound of the present invention (67.9 mg)having the following physical data.

TLC: Rf 0.41 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.90 (s, 1H), 10.04 (s, 1H), 9.42 (brs, 1H), 7.70 (s,1H), 7.60 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz,1H), 3.96 (m, 2H), 3.61 (t, J=11.4 Hz, 2H), 3.43-2.30 (m, 12H), 2.29 (s,3H), 1.63 (m, 8H).

EXAMPLE 28(1) TO EXAMPLE 28(42)

By the same procedure as described in Example 28, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 25(1) or the compound prepared in Example23(23), 23(24), 23(29), 23(37), 25, 25(2), 25(6) to 25(8), 25(11) to25(13), 26(2) or 26(5), and morpholine or a corresponding derivative,the following compounds of the present invention were obtained.

EXAMPLE 28(1)4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.22 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.90 (s, 1H), 10.12 (s, 1H), 9.54 (brs, 1H), 7.70 (s,1H), 7.59 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz,1H), 3.98 (m, 2H), 3.63 (t, J=11.6 Hz, 2H), 3.43-2.32 (m, 12H), 2.30 (s,3H), 1.95 (m, 2H), 1.64 (m, 4H).

EXAMPLE 28(2)4-(3-(N-(5-(4-methoxypiperidin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.29 (methanol:methylene chloride=2:3);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 10.04 (s, 1H), 8.95 (brs, 1H), 7.70 (s,1H), 7.59 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.8 Hz,1H), 3.52-2.33 (m, 13H), 3.24 (s, 3H), 2.29 (s, 3H), 2.15-1.46 (m, 12H).

EXAMPLE 28(3)4-(3-(N-(2-(2-(morpholin-4-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.50 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.91 (s, 1H), 10.00 (s, 1H), 9.78 (brs, 1H), 7.70 (s,1H), 7.64 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz,1H), 4.20 (s, 2H), 4.05-3.40 (m, 10H), 3.16 (m, 2H), 2.56-2.33 (m, 4H),2.31 (s, 3H), 1.70-1.59 (m, 4H).

EXAMPLE 28(4)4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.16 (chloroform:methanol=9:1);

NMR (DMSO-d₆): δ 10.53 (s, 1H), 10.15 (s, 1H), 9.59 (bs, 1H), 7.70 (s,1H), 7.58-7.55 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H),4.28-4.18 (m, 1H), 3.99-3.94 (m, 2H), 3.68-3.42 (m, 5H), 3.17-3.00 (m,5H), 2.90-2.80 (m, 2H), 2.74-2.64 (m, 1H), 2.43 (t, J=6.9 Hz, 2H),2.33-2.26 (m, 4H), 2.00-1.90 (m, 2H).

EXAMPLE 28(5)4-(3-(N-(5-(N′-(2-propynyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.30 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.03 (s, 1H), 8.93 (brs, 2H), 7.70 (s,1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz,1H), 3.92 (m, 2H), 3.72 (t, J=2.4 Hz, 1H), 2.96 (m, 2H), 2.48-2.32 (m,6H), 2.31 (s, 3H), 1.65 (m, 8H).

EXAMPLE 28(6)4-(3-(N-(5-(N′-(2-methyl-2-propenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.36 (methanol:methylene chloride:saturated aqueousammonia=1:9:0.1);

NMR (DMSO-d₆): δ 12.88 (brs, 1H), 10.07 (s, 1H), 8.54 (brs, 2H), 7.71(s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8Hz, 1H), 5.08 (s, 1H), 5.07 (s, 1H), 3.51 (t, J=6.0 Hz, 2H), 2.89 (m,2H), 2.48-2.34 (m, 9H), 1.77 (s, 3H), 1.69-1.59 (m, 8H).

EXAMPLE 28(7)4-(3-(N-(5-(1,2,3,6-tetrahydropyridin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.48 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.05 (s, 1H), 9.43 (brs, 1H), 7.70 (s,1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H),5.90 (m, 1H), 5.70 (m, 1H), 3.80 (m, 1H), 3.54 (m, 1H), 3.22-2.98 (m,4H), 2.60-2.18 (m, 8H), 2.50 (s, 3H), 1.82-1.50 (m, 8H).

EXAMPLE 28(8)4-(3-(N-(5-(N′-cyclopropylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.35 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.06 (s, 1H), 8.56 (brs, 2H), 7.70 (s,1H), 7.60 (m, 1H), 7.36 (dd, J=7.8, 7.8 Hz, 1H), 7.09 (m, 1H), 3.08-2.90(m, 2H), 2.69 (m, 1H), 2.56-2.20 (m, 6H), 2.34 (s, 3H), 1.80-1.46 (m,8H), 0.84-0.64 (m, 4H).

EXAMPLE 28(9)4-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.69 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 10.89 (s, 1H), 10.16 (s, 1H), 9.52 (br, 1H), 7.74 (s,1H), 7.61 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz,1H), 6.27 (s, 1H), 4.02-3.94 (m, 2H), 3.69-3.58 (m, 4H), 3.50-3.42 (m,2H), 3.20-3.01 (m, 6H), 2.48-2.42 (m, 2H), 2.02-1.92 (m, 2H).

EXAMPLE 28(10)4-(3-(N-(2-(2-(piperidin-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.30 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 10.19 (s, 2H), 7.83 (s, 1H), 7.79 (d,J=8.1 Hz, 1H), 7.38 (t, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.16 (s,2H), 3.85 (t, J=5.1 Hz, 2H), 3.28 (m, 2H), 2.58 (m, 2H), 2.48-2.35 (m,6H), 1.82-1.59 (m, 10H).

EXAMPLE 28(11)4-(3-(N-(2-(2-(pyrrolidin-1-yl)ethoxy)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.55 (methanol:methylene chloride:saturated aqueousammonia=1:9:0.1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.66 (brs, 1H), 10.17 (s, 1H), 7.86 (s,1H), 7.83 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz,1H), 4.16 (s, 2H), 3.82-3.55 (m, 4H), 3.38 (m, 2H), 3.03 (m, 2H),2.48-2.36 (m, 4H), 1.99-1.59 (m, 8H).

EXAMPLE 28(12)4-(3-(N-(5-(3-methoxypiperidin-1-yl)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.45 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.51 (brs, ½H), 10.24 (s, ½H), 10.20(s, ½H), 9.11 (brs, ½H), 7.73 (s, 1H), 7.64 (m, 1H), 7.35 (dd, J=7.8,7.8 Hz, 1H), 7.09 (m, 1H), 3.74-3.20 (m, 8H), 3.14-2.94 (m, 2H),2.80-2.24 (m, 8H), 2.16-1.10 (m, 10H).

EXAMPLE 28(13)4-(3-(N-(2-(morpholin-4-yl)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.44 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.92 (s, 1H), 10.92 (brs, 1H), 10.52 (brs, 1H), 7.71(s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.8Hz, 1H), 4.20-2.27 (m, 14H), 1.69 (m, 2H), 1.60 (m, 2H).

EXAMPLE 28(14)4-(3-(N-(2-(N′-(2-propynyl)amino)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.43 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.92 (s, 1H), 10.88 (s, 1H), 9.64 (brs, 2H), 7.69 (s,1H), 7.62 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz,1H), 4.02 (s, 2H), 3.97 (s, 2H), 3.76 (t, J=2.1 Hz, 1H), 2.48-2.35 (m,4H), 1.69 (m, 2H), 1.60 (m, 2H).

EXAMPLE 28(15)4-(3-(N-(2-(N′-cyclobutylamino)acetyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.40 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.92 (s, 1H), 10.81 (s, 1H), 9.29 (m, 2H), 7.69 (s,1H), 7.63 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz,1H), 3.85-3.71 (m, 3H), 2.45-2.13 (m, 8H), 1.80-1.61 (m, 6H).

EXAMPLE 28(16)4-(3-(N-(3-(morpholin-4-yl)propanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.41 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 10.57 (brs, 1H), 10.42 (s, 1H), 7.70 (s,1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz,1H), 3.96 (m, 2H), 3.74 (t, J=11.5 Hz, 2H), 3.42-3.33 (m, 4H), 3.09 (m,2H), 2.92 (t, J=7.5 Hz, 2H), 2.48-2.34 (m, 4H), 1.69 (m, 2H), 1.60 (m,2H).

EXAMPLE 28(17)4-(3-(N-(3-(N′-(2-propynyl)amino)propanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.40 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 10.43 (s, 1H), 9.37 (brs, 2H), 7.72 (s,1H), 7.61 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz,1H), 3.93-3.71 (m, 3H), 3.25 (m, 2H), 2.83 (t, J=6.9 Hz, 2H), 2.48-2.34(m, 4H), 1.69 (m, 2H), 1.59 (m, 2H).

EXAMPLE 28(18)4-(3-(N-(4-(N′-(2-propynyl)amino)butanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.25 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.89 (s, 1H), 10.24 (s, 1H), 9.35 (brs, 2H), 7.70 (s,1H), 7.62 (d, J=8.1 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.10 (d, J=8.1 Hz,1H), 3.91 (d, J=2.7 Hz, 2H), 3.70 (t, J=2.7 Hz, 1H), 3.00 (m, 2H), 2.44(m, 4H), 2.34 (m, 2H), 1.92 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H).

EXAMPLE 28(19)8-(3-(N-(4-(morpholin-4-yl)butanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedihydro chloride

TLC: Rf 0.54 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.34 (brs, 1H), 11.04 (brs, 1H), 10.31 (s, 1H),7.78-7.64 (m, 2H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.11 (m, 1H), 4.02-3.70(m, 4H), 3.50-3.32 (m, 2H), 3.24-2.90 (m, 6H), 2.60-2.34 (m, 4H),2.12-1.90 (m, 2H), 1.82-1.62 (m, 2H).

EXAMPLE 28(20)4-(2-(N-(2-(pyrrolidin-1-yl)acetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.43 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 7.77 (t, J=5.7 Hz, 1H), 3.42-3.26 (m,2H), 2.97 (s, 2H), 2.63 (t, J=6.9 Hz, 2H), 2.54-2.28 (m, 8H), 1.76-1.52(m, 8H).

EXAMPLE 28(21)4-(N-(2-(N′-cyclobutylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.21 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (br, 1H), 7.97 (t, J=6.0 Hz, 1H), 3.40 (s, 2H),3.18-3.03 (m, 3H), 2.52-2.45 (m, 2H), 2.44-2.32 (m, 4H), 2.12-2.02 (m,2H), 1.78-1.56 (m, 8H).

EXAMPLE 28(22)4-(N-(2-(azepan-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.29 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.58 (br, 1H), 7.82 (t, J=6.0 Hz, 1H), 3.39 (s, 2H),3.10 (q, J=6.0 Hz, 2H), 2.60-2.52 (m, 4H), 2.52-2.45 (m, 2H), 2.44-2.33(m, 4H), 1.68-1.60 (m, 4H), 1.58-1.46 (m, 8H).

Hydrochloride:

TLC: Rf 0.34 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 10.44 (br, 1H), 8.49 (m, 1H), 3.51-3.42(m, 2H), 3.47 (s, 2H), 3.42-3.31 (m, 2H), 3.18-3.03 (m, 4H), 2.46-2.34(m, 4H), 1.88-1.76 (m, 4H), 1.72-1.50 (m, 8H).

EXAMPLE 28(23)4-(2-(N-(3-(N′-cyclobutylamino)propanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.17 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.55 (brs, 1H), 7.99 (t, J=5.4 Hz, 1H), 4.08 (br, 1H),3.46-3.20 (m, 2H), 3.09 (m, 1H), 2.68-2.28 (m, 8H), 2.13 (t, J=6.9 Hz,2H), 2.04 (m, 2H), 1.80-1.40 (m, 8H).

EXAMPLE 28(24)4-(2-(N-(3-(piperidin-1-yl)propanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.26 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.55 (s, 1H), 8.05 (t, J=5.4 Hz, 1H), 3.42-3.24 (m,4H), 2.60 (t, J=7.2 Hz, 2H), 2.56-2.22 (m, 8H), 2.18 (t, J=7.2 Hz, 2H),1.76-1.54 (m, 4H), 1.52-1.24 (m, 6H).

EXAMPLE 28(25)4-(N-(2-(N′-methyl-N′-isopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.25 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 7.84 (m, 1H), 3.39 (s, 2H), 3.09 (q,J=6.0 Hz, 2H), 2.72 (m, 1H), 2.46-2.30 (m, 6H), 2.10 (s, 3H), 1.66-1.60(m, 4H), 0.89 (d, J=6.6 Hz, 6H).

EXAMPLE 28(26)4-(N-(2-(N′-cyclopropylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.43 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 7.93 (m, 1H), 3.40 (s, 2H), 3.12 (q,J=6.0 Hz, 2H), 2.61 (t, J=6.0 Hz, 2H), 2.44-2.32 (m, 2H), 2.04 (m, 1H),1.68-1.60 (m, 4H), 0.37-0.30 (m, 2H), 0.20-0.14 (m, 2H).

EXAMPLE 28(27)4-(N-(3-(piperidin-1-yl)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.70 (s, 1H), 8.00 (m, 1H), 3.38 (s, 2H), 3.04 (q,J=6.3 Hz, 2H), 2.46-2.33 (m, 4H), 2.32-2.16 (m, 6H), 1.68-1.60 (m, 4H),1.59-1.42 (m, 6H), 1.41-1.30 (m, 2H).

EXAMPLE 28(28)4-(N-(2-(N′-cyclopentylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.35 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.62 (s, 1H), 8.44 (m, 2H), 8.21 (t, J=6.0 Hz, 1H),3.46 (m, 1H), 3.46 (s, 2H), 3.38-3.26 (m, 2H), 300-2.92 (m, 2H),2.45-2.34 (m, 4H), 2.00-1.86 (m, 2H), 1.74-1.60 (m, 6H), 1.60-1.48 (m,4H).

EXAMPLE 28(29)4-(N-(3-(N′-cyclobutylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.30 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 8.53 (m, 2H), 8.19 (t, J=6.0 Hz, 1H),3.65 (quin, J=7.8 Hz, 1H), 3.42 (s, 2H), 3.12 (q, J=6.0 Hz, 2H),2.80-2.70 (m, 2H), 2.45-2.36 (m, 4H), 2.20-2.00 (m, 4H), 1.84-1.60 (m,8H).

EXAMPLE 28(30)4-(N-(4-(N′-cyclobutylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.26 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 8.53 (br, 2H), 8.09 (t, J=6.0 Hz, 1H),3.64 (quin, J=6.0 Hz, 1H), 3.40 (s, 2H), 3.06, (q, J=6.0 Hz, 2H),2.82-2.70 (m, 2H), 2.46-2.33 (m, 4H), 2.22-2.02 (m, 4H), 1.84-1.72 (m,2H), 1.70-1.60 (m, 4H), 1.60-1.38 (m, 4H).

EXAMPLE 28(31)4-(N-(2-(N′-cyclohexylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.18 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.62 (br, 1H), 8.40-8.20 (m, 2H), 8.22 (m, 1H), 3.45(s, 2H), 3.30 (m, 1H), 3.03-2.90 (m, 2H), 2.43-2.32 (m, 4H), 2.00-1.90(m, 2H), 1.78-1.54 (m, 8H), 1.28-1.00 (m, 6H).

EXAMPLE 28(32)4-(N-(4-(N′-methylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.063 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.28-8.00 (br, 2H), 8.10 (m, 1H), 3.40(s, 2H), 3.05 (q, J=6.0 Hz, 2H), 2.86 (t, J=7.2 Hz, 2H), 2.52 (s, 3H),2.48-2.32 (m, 4H), 1.70-1.60 (m, 4H), 1.60-1.36 (m, 4H).

EXAMPLE 28(33)4-(N-(4-(N′-cyclopentylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.28 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.58 (s 1H), 8.37 (br, 2H), 8.11 (m, 1H), 3.43 (m,1H), 3.41 (s, 2H), 3.07 (q, J=6.0 Hz, 2H), 2.92-2.83 (m, 2H), 2.46-2.33(m, 4H), 2.00-1.88 (m, 2H), 1.74-1.40 (m, 14H).

EXAMPLE 28(34)4-(N-(3-(N′-cyclopentylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.61 (s 1H), 8.30-8.00 (br, 2H), 8.22 (m, 1H), 3.43(s, 2H), 3.43 (m, 1H), 3.14 (q, J=6.6 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H),2.46-2.34 (m, 4H), 1.96-1.84 (m, 2H), 1.80-1.46 (m, 12H).

EXAMPLE 28(35)4-(N-(4-(N′-cyclohexylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrobromide

TLC: Rf 0.56 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.58 (s 1H), 8.24 (br, 2H), 8.10 (m, 1H), 3.40 (s,2H), 3.07 (q, J=6.3 Hz, 2H), 3.00-2.84 (m, 3H), 2.46-2.34 (m, 4H),2.04-1.95 (m, 2H), 1.80-1.40 (m, 11H), 1.28-1.10 (m, 5H).

EXAMPLE 28(36)4-(N-(3-(N′-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.59 (s 1H), 8.09 (t, J=6.0 Hz, 1H), 3.40 (s, 2H),3.09 (q, J=6.0 Hz, 2H), 2.74 (t, J=5.2 Hz, 2H), 2.46-2.25 (m, 5H),1.70-1.55 (m, 6H), 0.58-0.50 (m, 2H), 0.50-0.40 (m, 2H).

EXAMPLE 28(37)4-(N-(4-(N′-cyclopropylamino)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.56 (brs 1H), 8.01 (t, J=6.0 Hz, 1H), 3.38 (s, 2H),3.18-2.98 (m, 2H), 2.60-2.52 (m, 2H), 2.46-2.32 (m, 4H), 2.06 (m, 1H),1.70-1.60 (m, 4H), 1.44-1.35 (m, 4H), 0.40-0.34 (m, 2H), 0.26-0.18 (m,2H).

EXAMPLE 28(38)4-(N-methyl-N-(3-(N′-cyclohexylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.62 and 8.42 (br, 2H), 3.68 (s, 2H),3.43-3.34 (m, 2H), 3.02 and 2.82 (s, 3H), 3.00-2.78 (m, 3H), 2.42-2.32(m, 4H), 2.02-1.54 (m, 12H), 1.32-1.17 (m, 4H).

EXAMPLE 28(39)4-(N-methyl-N-(3-(N′-cyclopentylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.20 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.73 and 8.49 (br, 2H), 3.68 and 3.67(s, 2H), 3.46-3.36 (m, 3H), 3.01 and 2.82 (s, 3H), 2.98-2.78 (m, 2H),2.42-2.34 (m, 4H), 1.98-1.76 (m, 4H), 1.70-1.44 (m, 10H).

EXAMPLE 28(40)4-(N-methyl-N-(3-(N′-cyclobutylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.24 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.63 (br, 2H), 3.67 and 3.65 (s, 2H),3.62 (m, 1H), 3.44-3.30 (m, 2H), 3.00 and 2.81 (s, 3H), 2.82-2.67 (m,2H), 2.41-2.32 (m, 4H), 2.20-2.04 (m, 4H), 1.90-1.70 (m, 4H), 1.70-1.60(m, 4H).

EXAMPLE 28(41)4-(N-methyl-N-(3-(N′-cyclopropylamino)propyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.24 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.59 and 12.57 (s, 1H), 8.57 (br, 2H), 3.67 (s, 2H),3.46-3.30 (m, 2H), 3.01 and 2.81 (s, 3H), 2.95-2.82 (m, 2H), 2.57 (m,1H), 2.41-2.33 (m, 4H), 1.95-1.75 (m, 2H), 1.70-1.58 (m, 4H), 0.81-0.72(m, 2H), 0.72-0.64 (m, 2H).

EXAMPLE 28(42)4-(N-(4-(morpholin-4-yl)butyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.38 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.00 (t, J=5.4 Hz, 1H), 3.55 (m, 4H),3.39 (s, 2H), 3.29-2.20 (m, 12H), 1.63 (brs, 4H), 1.40 (brs, 4H).

Hydrochloride:

TLC: Rf 0.37 (methanol:methylene chloride:saturated aqueousammonia=1:9:0.1);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 10.34 (brs, 1H), 8.13 (t, J=5.4 Hz, 1H),3.94 (m, 2H), 3.72 (t, J=11.4 Hz, 2H), 3.41 (s, 2H), 3.38 (m, 2H), 3.07(m, 6H), 2.39 (m, 4H), 1.63-1.40 (m, 8H).

Methanesulfonate:

TLC: Rf 0.34 (methanol:methylene chloride:28% ammonia water=1:9:0.1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 9.54 (brs, 1H), 8.10 (t, J=5.4 Hz, 1H),4.00-3.94 (m, 2H), 3.69-3.61 (m, 2H), 3.41 (s, 2H), 3.36 (m, 2H),3.11-2.97 (m, 6H), 2.42-2.33 (m, 4H), 2.34 (s, 3H), 1.63 (m, 6H),1.48-1.38 (m, 2H).

EXAMPLE 294-(3-(N-(5-aminopentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

Under an atmosphere of hydrogen, a mixture of the compound prepared inExample 26(4) (430 mg) and 10% palladium on carbon (86.0 mg) in methanol(5.0 mL) was stirred at room temperature for 10 hours. The reactionmixture was filtrated through Celite. The filtrate was concentrated. Theobtained powder was recrystallized from ethyl acetate to give a freeform of the title compound (268 mg). A suspension of the obtained freeform (264 mg) and methanesulfonate (74.6 mg) in methanol (3.0 mL) wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated to give the compound of the present invention (307 mg)having the following physical data.

TLC: Rf 0.28 (methanol:methylene chloride:saturated aqueousammonia=4:8:0.1);

NMR (CD₃OD): δ 7.80 (s, 1H), 7.66 (m, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.22(m, 1H), 3.01 (brt, J=6.8 Hz, 2H), 2.75 (s, 3H), 2.68 (brt, J=6.0 Hz,2H), 2.53 (m, 4H), 1.90-1.74 (m, 8H).

EXAMPLE 29(1) TO EXAMPLE 29(6)

By the same procedure as described in Example 29, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 26(6) to 26(8), 26(12), 24(31) or 27(38)instead of the compound prepared in Example 26(4), the followingcompounds of the present invention were obtained.

EXAMPLE 29(1)4-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-7,8,9,9a-tetrahydro-2H-pyrido[1,2-d][1,2,4]triazin-1(6H)-onemethanesulfonate

TLC: Rf 0.34 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (CD₃OD): δ 10.02 (brs, 1H), 7.78 (s, 1H), 7.65 (d, J=7.8 Hz, 1H),7.45 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.07 (m, 1H), 3.47 (m,1H), 3.07 (t, J=6.9 Hz, 2H), 2.91 (m, 1H), 2.75 (s, 6H), 2.53 (t, J=6.6Hz, 2H), 2.29-1.52 (m, 10H).

EXAMPLE 29(2)4-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.26 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (CD₃OD): δ 8.14 (t, J=1.8 Hz, 1H), 7.78 (m, 1H), 7.64 (t, J=7.8 Hz,1H), 7.39 (m, 1H), 4.68 (dd, J=11.1, 2.4 Hz, 1H), 4.00 (dt, J=14.1, 3.0Hz, 1H), 3.53-3.34 (m, 2H), 3.10 (m, 4H), 2.76 (s, 6H), 2.57 (m, 3H),1.84 (m, 4H).

EXAMPLE 29(3)4-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-1-onemethanesulfonate

TLC: Rf 0.29 (chloroform:methanol:28% ammonia water=40:10:1);

NMR (DMSO-d₆): δ 12.96 (br-s, 1H), 10.05 (s, 1H), 8.22 (br-s, 2H), 7.69(m, 1H), 7.57 (m, 1H), 7.37 (m, 1H), 7.00 (m, 1H), 2.92-2.78 (m, 4H),2.58-2.52 (m, 5H), 2.40-2.32 (m, 2H), 2.30 (s, 3H), 1.86-1.76 (m, 2H),1.66-1.46 (m, 8H).

EXAMPLE 29(4)4-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 10.89 (s, 1H), 10.37 (br, 1H), 8.83 (br, 2H), 7.76 (s,1H), 7.68 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz,1H), 6.26 (s, 1H), 3.64-3.58 (m, 2H), 3.20-3.14 (m, 2H), 2.94-2.84 (m,2H), 2.54-2.30 (m, 5H), 1.70-1.60 (m, 4H).

EXAMPLE 29(5)4-(N-(2-(piperidin-4-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.14 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.1);

NMR (DMSO-d₆): δ 12.54 (brs, 1H), 8.44 (s, 1H), 8.01 (t, J=5.4 Hz, 1H),3.38 (s, 2H), 3.08-2.26 (m, 12H), 1.63 (brs, 4H), 1.34-1.00 (m, 5H).

Methanesulfonate:

TLC: Rf 0.43 (methylene chloride:methanol:28% ammonia water=6:3:1);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.18 (brs, 2H), 8.02 (t, J=5.4 Hz,1H), 3.38 (s, 2H), 3.22 (m, 2H), 3.08 (m, 2H), 2.76 (m, 2H), 2.46-2.34(m, 4H), 2.30 (s, 3H), 1.77 (m, 2H), 1.63 (m, 4H), 1.50 (m, 1H),1.40-1.24 (m, 4H).

EXAMPLE 29(6)4-(2-(1,4-diazepan-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.083 (methylene chloride:methanol=4:1);

NMR (DMSO-d₆): δ 12.5 (brs, 1H), 2.80-2.55 (m, 12H), 2.49 (m, 2H), 2.35(m, 2H), 1.75-1.68 (m, 6H).

EXAMPLE 304-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

4N hydrogen chloride in dioxane (2.50 mL) was added dropwise to asolution of the compound prepared in Example 26 (290 mg) in methanol(3.0 mL) in ice bath, the mixture was stirred at room temperature for 2hours. The reaction mixture was concentrated. The residue was purifiedby column chromatography on silica gel (methanol:methylenechloride=1:9→methanol:methylene chloride:saturated aqueousammonia=2:8:0.1). 1N sodium hydroxide solution (0.34 mL) was addeddropwise to a suspension of the obtained solid (134 mg) in methanol (1.0mL) and the mixture was stirred at room temperature for 30 minutes. Asaturated aqueous ammonium chloride solution was added to the reactionmixture, which was extracted with methylene chloride. The extract waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated. A solution of the obtained solid (64.8 mg) andmethanesulfonate (17.6 mg) in methanol (3.0 mL) was stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated togive the compound of the present invention (82.4 mg) having thefollowing physical data.

TLC: Rf 0.27 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.5);

NMR (CD₃OD): δ 10.00 (brs, 1H), 7.75 (d, J=1.2 Hz, 1H), 7.63 (dd, J=8.1,1.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 3.07 (brt,J=7.2 Hz, 2H), 2.74 (s, 6H), 2.65 (brt, J=6.3 Hz, 2H), 2.52 (m, 4H),1.82 (m, 8H).

EXAMPLE 30(1) TO EXAMPLE 30(19)

By the same procedure as described in Example 30, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 26(9), 26(10), 26(11), 23, 26(14), 26(15),23(3), 23(4), 23(9), 23(16), 26(16), 27(7), 23(21), 26(17), 27(14),26(19), 23(25), 23(33) or 24(48) instead of the compound prepared inExample 26, the following compounds of the present invention wereobtained.

EXAMPLE 30(1)4-(3-(N-(4-(N′-methylamino)butanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.20 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 10.56 (s, 1H), 10.17 (s, 1H), 8.45 (br, 2H), 7.71 (s,1H), 7.58 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz,1H), 4.24 (dd, J=8.4, 4.5 Hz, 1H), 3.56 (m, 1H), 3.09 (m, 1H), 2.98-2.90(m, 2H), 2.88-2.84 (m, 2H), 2.71 (m, 1H), 2.56 (t, J=6.0 Hz, 3H), 2.44(t, J=6.0 Hz, 2H), 2.31 (s, 3H), 2.31 (m, 1H), 1.94-1.86 (m, 2H).

EXAMPLE 30(2)4-(3-(N-(6-(N′-methylamino)hexanoyl)amino)phenyl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-onemethanesulfonate

TLC: Rf 0.17 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 10.54 (s, 1H), 10.05 (s, 3H), 8.36 (br, 2H), 7.71 (s,1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.06 (d, J=7.5 Hz,1H), 4.24 (m, 1H), 3.59 (m, 1H), 3.08 (m, 1H), 2.92-2.82 (m, 2H), 2.71(m, 1H), 2.60-2.40 (m, 3H), 2.31 (m, 1H), 2.293 (s, 3H), 2.289 (s, 3H),1.68-1.55 (m, 4H), 1.40-1.30 (m, 2H).

EXAMPLE 30(3)4-(3-(N-(5-(N′-(3-methyl-2-butenyl)amino)pentanoyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.88 (s, 1H), 10.24 (s, 1H), 8.84 (s, 2H), 7.73 (s,1H), 7.64 (m, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.08 (m, 1H), 5.25 (t,J=7.2 Hz, 1H), 3.56-3.40 (m, 2H), 2.98-2.72 (m, 2H), 2.60-2.24 (m, 6H),1.80-1.50 (m, 14H).

EXAMPLE 30(4)4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.19 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 7.98 (m, 1H), 3.41 (s, 2H), 3.03 (q, J=6.6 Hz, 2H),2.55 (t, J=6.6 Hz, 2H), 2.46-2.33 (m, 4H), 1.70-1.60 (m, 4H).

Hydrochloride:

TLC: Rf 0.44 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (DMSO-d₆): δ 12.60 (brs, 1H), 8.42 (t, J=6.0 Hz, 1H), 8.11 (brs,3H), 3.46 (s, 2H), 3.31 (q, J=6.0 Hz, 2H), 2.84 (q, J=6.0 Hz, 2H), 2.39(m, 4H), 1.63 (m, 4H).

EXAMPLE 30(5)4-(3-(N-(azetidin-3-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.18 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 10.43 (s, 1H), 9.10 (brs, 1H), 8.82 (brs, 1H), 7.73 (m,1H), 7.64 (m, 1H), 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.14 (m, 1H), 4.20-3.92(m, 4H), 3.79 (m, 1H), 2.62-2.20 (m, 4H), 1.78-1.50 (m, 4H).

EXAMPLE 30(6)4-(3-(N-(pyrrolidin-2-ylcarbonyl)amino)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.53 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 12.91 (s, 1H), 10.86 (s, 1H), 9.65 (brs, 1H), 8.67(brs, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H),7.19 (d, J=7.8 Hz, 1H), 4.37 (m, 1H), 3.27-2.26 (m, 6H), 1.94 (m, 4H),1.70-1.59 (m, 4H).

EXAMPLE 30(7)4-(N-(3-aminopropyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.41 (ethyl acetate:acetic acid:water=3:3:1);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.23 (br, 1H), 7.88 (br, 3H), 3.42 (s,2H), 3.11 (q, J=6.6 Hz, 2H), 2.76 (q, J=6.6 Hz, 2H), 2.50-2.32 (m, 4H),1.76-1.60 (m, 6H).

EXAMPLE 30(8)4-(N-(2-(N′-methylamino)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.29 (ethyl acetate:acetic acid:water=3:3:1);

NMR (DMSO-d₆): δ 12.60 (brs, 1H), 8.86 (br, 2H), 8.38 (br, 1H), 3.47 (s,2H), 3.35 (q, J=6.0 Hz, 2H), 2.94 (quin, J=6.0 Hz, 2H), 2.53 (t, J=5.4Hz, 3H), 2.50-2.34 (m, 4H), 1.70-1.60 (m, 4H).

EXAMPLE 30(9)4-(1-(N-(2-aminoethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.62 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (DMSO-d₆): δ 12.62 (s, 1H), 8.25 (t, J=5.4 Hz, 1H), 8.00 (brs, 3H),3.73 (q, J=6.9 Hz, 1H), 3.26 (m, 2H), 2.83 (m, 2H), 2.48-2.30 (m, 4H),1.64 (m, 4H), 1.31 (d, J=6.9 Hz, 3H).

EXAMPLE 30(10)4-(N-(4-aminobutyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.15 (ethyl acetate:acetic acid:water=3:1:1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 8.17 (t, J=6.3 Hz, 1H), 7.95 (br, 3H),3.41 (s, 2H), 3.05 (q, J=6.3 Hz, 2H), 2.75 (m, 2H), 2.46-2.33 (m, 4H),1.68-1.60 (m, 4H), 1.60-1.40 (m, 4H).

EXAMPLE 30(11)4-(2-(N-(2-aminoacetyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.11 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.58 (brs, 1H), 8.59 (t, J=5.7 Hz, 1H), 8.19 (brs,3H), 3.56-3.28 (m, 4H), 2.65 (t, J=7.2 Hz, 2H), 2.54-2.28 (m, 4H),1.76-1.54 (m, 4H).

EXAMPLE 30(12)4-(2-(piperazin-1-yl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.15 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 3.80-3.50 (m, 10H), 3.14 (t, J=7.5 Hz, 2H), 2.64-2.50 (m,4H), 1.90-1.74 (m, 4H).

EXAMPLE 30(13)4-(1-(N-(4-aminobutyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.19 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.04 (t, J=5.4 Hz, 1H), 7.83 (brs, 3H),3.69 (q, J=7.2 Hz, 1H), 3.09 (m, 2H), 2.74 (m, 2H), 2.48-2.25 (m, 4H),1.64-1.42 (m, 8H), 1.31 (d, J=7.2 Hz, 3H).

EXAMPLE 30(14)4-(2-(N-(3-aminopropanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.11 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.24 (t, J=5.7 Hz, 1H), 7.94 (brs,3H), 3.42-3.24 (m, 2H), 3.04-2.84 (m, 2H), 2.63 (t, J=7.2 Hz, 2H),2.56-2.28 (m, 6H), 1.76-1.52 (m, 4H).

EXAMPLE 30(15)4-(2-(N-(2-aminoethyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onedihydrochloride

TLC: Rf 0.10 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.1);

NMR (DMSO-d₆): δ 12.69 (s, 1H), 9.63 (brs, 2H), 8.41 (brs, 3H),3.78-3.06 (m, 6H), 2.94 (t, J=7.5 Hz, 2H), 2.58-2.30 (m, 4H), 1.78-1.54(m, 4H).

EXAMPLE 30(16)4-(2-(N-(4-aminobutanoyl)amino)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.10 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 8.09 (m, 4H), 3.36-3.20 (m, 2H),2.82-2.66 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.54-2.28 (m, 4H), 2.15 (t,J=7.2 Hz, 2H), 1.84-1.52 (m, 6H).

EXAMPLE 30(17)4-(N-(5-aminopentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.34 (chloroform:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (br, 1H), 8.09 (m, 1H), 7.87 (br, 2H), 3.40 (s,2H), 3.03 (q, J=6.0 Hz, 2H), 2.80-2.66 (m, 2H), 2.46-2.33 (m, 4H),1.70-1.60 (m, 4H), 1.60-1.49 (m, 2H), 1.48-1.36 (m, 2H), 1.36-1.26 (m,2H).

EXAMPLE 30(18)4-(2-(N-(2-aminoethyl)carbamoyl)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.18 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.52 (s, 1H), 8.20 (t, J=5.4 Hz, 1H), 8.02 (brs, 3H),3.36-3.20 (m, 2H), 2.92-2.76 (m, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.54-2.28(m, 6H), 1.76-1.54 (m, 4H).

EXAMPLE 30(19)8-(N-(3-aminopropyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedihydrochloride

TLC: Rf 0.25 (methanol:acetic acid=5:1);

NMR (DMSO-d₆): δ 12.24 (s, 1H), 8.41 (t, J=5.4 Hz, 1H), 7.94 (brs, 5H),3.42 (s, 2H), 3.20 (t, J=5.4 Hz, 2H), 3.12 (m, 2H), 2.78 (m, 2H), 2.37(t, J=6.0 Hz, 2H), 1.69 (m, 4H).

EXAMPLE 31 4-(2-acetylthioethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of the compound prepared in Reference example 13 (650 mg)in dimethylformamide (15 mL) were added potassium thioacetate (698 mg)and potassium carbonate (422 mg) and the mixture was stirred at 50° C.for 2 hours. After cooling to room temperature, the reaction mixture waspoured in cold water and extracted with ethyl acetate. The extract waswashed with water and brine sequentially, dried over anhydrous magnesiumsulfate and concentrated to give the compound of the present invention(688 mg) having the following physical data.

TLC: Rf 0.40 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 3.11 (t, J=7.2 Hz, 2H), 2.75 (t, J=7.2Hz, 2H), 2.56-2.28 (m, 4H), 2.31 (s, 3H), 1.76-1.54 (m, 4H).

EXAMPLE 31(1)8-(2-acetylthioethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

By the same procedure as described in Example 31 using a correspondingderivative instead of the compound prepared in Reference example 13, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.43 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 11.82 (s, 1H), 6.32 (s, 1H), 3.16 (m, 2H), 3.09 (t,J=7.2 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 2.31 (s,3H), 1.69 (m, 2H).

EXAMPLE 32 4-(2-benzylthioethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a suspension of the compound prepared in Example 31 (100 mg) inmethanol (4.0 mL) were added benzyl bromide (0.06 mL) and potassiumcarbonate (82 mg) and the mixture was stirred at room temperature for 2hours. The reaction mixture was poured in cold 0.5N hydrochloric acidand extracted with ethyl acetate. The extract was washed with brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (methylenechloride:methanol=70:1→30:1) to give the compound of the presentinvention (47 mg) having the following physical data.

TLC: Rf 0.42 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.54 (s, 1H), 7.38-7.16 (m, 5H), 3.77 (s, 2H),2.80-2.58 (m, 4H), 2.50-2.26 (m, 4H), 1.76-1.52 (m, 4H).

EXAMPLE 32(1) TO EXAMPLE 32(2)

By the same procedure as described in Example 32, if necessary, byconverting to corresponding salts by conventional method, using acorresponding derivative instead of benzyl bromide, the followingcompounds of the present invention were obtained.

EXAMPLE 32(1)4-(2-(3-(piperidin-1-yl)propylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.57 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 2.78-2.70 (m, 4H), 2.58-2.20 (m, 12H),1.76-1.56 (m, 6H), 1.54-1.26 (m, 6H).

EXAMPLE 32(2)4-(2-(2-(piperidin-1-yl)ethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.28 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 2.82-2.70 (m, 4H), 2.68-2.56 (m, 2H),2.54-2.22 (m, 10H), 1.76-1.55 (m, 4H), 1.54-1.26 (m, 6H).

Hydrochloride:

TLC: Rf 0.28 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 10.22 (brs, 1H), 3.44 (m, 2H), 3.19 (m,2H), 3.04-2.68 (m, 8H), 2.62-2.28 (m, 4H), 1.90-1.54 (m, 9H), 1.35 (m,1H).

EXAMPLE 334-(2-(2-hydroxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one(300 mg; It was prepared by the same procedure as described in Example32 using 1-t-butyldimethylsilyloxy-2-iodoethane instead of benzylbromide.) in tetrahydrofuran (4.0 mL) was added tetrabutylammoniumfluoride (638 mg) and the mixture was stirred at room temperatureovernight. The reaction mixture was poured in a cold saturated aqueousammonium chloride solution and extracted with ethyl acetate. The extractwas washed with brine, dried over magnesium sulfate and concentrated.The residue was washed with t-butyl methyl ether to give the compound ofthe present invention (191 mg) having the following physical data.

TLC: Rf 0.36 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 4.77 (t, J=5.4 Hz, 1H), 3.53 (dt, J=5.4,6.6 Hz, 2H), 2.84-2.72 (m, 4H), 2.59 (t, J=6.6 Hz, 2H), 2.56-2.28 (m,4H), 1.76-1.54 (m, 4H).

EXAMPLE 33(1) TO EXAMPLE 33(3)

By the same procedure as described in Example 33 using4-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,8-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneor8-(2-(3-t-butyldimethylsilyloxypropylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneinstead of4-(2-(2-t-butyldimethylsilyloxyethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,the following compounds of the present invention were obtained.

EXAMPLE 33(1)4-(2-(3-hydroxypropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 4.46 (t, J=5.1 Hz, 1H), 3.44 (dt, J=5.1,6.9 Hz, 2H), 2.80-2.68 (m, 4H), 2.56 (t, J=7.2 Hz, 2H), 2.54-2.30 (m,4H), 1.76-1.54 (m, 6H).

EXAMPLE 33(2)8-(2-(2-hydroxyethylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.31 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 11.78 (s, 1H), 6.33 (s, 1H), 4.78 (t, J=5.4 Hz, 1H),3.53 (dt, J=5.4, 6.6 Hz, 2H), 3.17 (m, 2H), 2.84-2.60 (m, 4H), 2.59 (t,J=6.6 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H).

EXAMPLE 33(3)8-(2-(3-hydroxypropylthio)ethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.32 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 11.77 (s, 1H), 6.33 (s, 1H), 4.46 (t, J=5.1 Hz, 1H),3.44 (dt, J=5.1, 5.7 Hz, 2H), 3.16 (m, 2H), 2.80-2.60 (m, 4H), 2.55 (t,J=7.2 Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.78-1.50 (m, 4H).

EXAMPLE 344-(2-(2-bromoethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of the compound prepared in Example 33 (160 mg) inchloroform (5.0 mL) were added triphenylphosphine (248 mg) and carbontetrabromide (313 mg), and the mixture was stirred at room temperaturefor 2 hours. Methanol (1.0 mL) was added dropwise to the reactionmixture, which was stirred for 5 minutes and concentrated. The residuewas purified by column chromatography on silica gel (methylenechloride:methanol=80:1→50:1) to give a crude compound of the presentinvention (598 mg) having the following physical data. The obtainedcompound was used in next reaction without purifying.

TLC: Rf 0.49 (chloroform:methanol=8:1);

NMR (CD₃OD): δ 3.55 (t, J=6.3 Hz, 2H), 2.96-2.82 (m, 4H), 2.72 (t, J=6.3Hz, 2H), 2.64-2.44 (m, 4H), 1.86-1.70 (m, 4H).

EXAMPLE 354-(2-(3-chloropropylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a suspension of the compound prepared in Example 33(1) (110 mg) inmethylene chloride (2.1 mL) were added thionyl chloride (0.08 mL) andpyridine (0.01 mL), and the mixture was stirred at room temperature for1 day. The reaction mixture was poured in cold water and extracted withmethylene chloride. The extract was washed with a saturated aqueoussodium hydrogen carbonate solution and brine sequentially, dried overanhydrous magnesium sulfate and concentrated to give the compound of thepresent invention (109 mg) having the following physical data.

TLC: Rf 0.49 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.82-2.72 (m,4H), 2.64 (t, J=6.9 Hz, 2H), 2.54-2.30 (m, 4H), 1.95 (tt, J=6.9, 6.3 Hz,2H), 1.76-1.54 (m, 4H).

EXAMPLE 36 TO EXAMPLE 36(1)

By the same procedure as described in Example 28, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 34 or 35 instead of the compound preparedin Example 25(1) and cyclopentylamine instead of morpholine, thefollowing compounds of the present invention were obtained.

EXAMPLE 364-(2-(2-(N-cyclopentylamino)ethylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.36 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.56 (brs, 1H), 3.00 (quint, J=6.3 Hz, 1H), 2.82-2.72(m, 4H), 2.71-2.28 (m, 8H), 1.80-1.16 (m, 12H).

EXAMPLE 36(1)4-(2-(3-(N-cyclopentylamino)propylthio)ethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.38 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.99 (brs, 2H), 3.41 (m, 1H), 2.92 (m,2H), 2.84-2.70 (m, 4H), 2.63 (t, J=7.2 Hz, 2H), 2.58-2.28 (m, 4H),2.06-1.38 (m, 14H).

EXAMPLE 378-(3-(N-(5-(N′-methylamino)pentanoyl)amino)phenyl)-2,3,4,6-tetrahydropyrazino[2,3-d]pyridazin-5(1H)-onemethanesulfonate

By the same procedure as described in Reference example 1→Example1→Example 26→Example 29 using furo[3,4-d]pyrazine-5,7-dione instead of4,5,6,7-tetrahydro-2-benzofuran-1,3-dione, the compound of the presentinvention having the following physical data was obtained.

TLC: Rf 0.17 (methanol:methylene chloride:saturated aqueousammonia=1:4:0.2);

NMR (CD₃OD): δ 7.81 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.8 Hz,1H), 7.32 (d, J=7.8 Hz, 1H), 3.50 (m, 2H), 3.39 (m, 2H), 3.08 (m, 2H),2.75 (s, 3H), 2.74 (s, 3H), 2.53 (m, 2H), 1.81 (m, 4H).

EXAMPLE 384-(N-(2-(1H-tetrazol-5-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A mixture of the compound prepared in Example 23(34) (180 mg),trimethyltin azide (285 mg) and toluene (1.5 mL) was refluxed overnight.The reaction mixture was concentrated. The residue was washed with ethylacetate and hot methanol sequentially to give the compound of thepresent invention (113 mg) having the following physical data.

TLC: Rf 0.14 (methylene chloride:methanol:saturated aqueousammonia=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.19 (t, J=6.0 Hz, 1H), 3.44 (q, J=6.0Hz, 2H), 3.37 (s, 2H), 3.02 (t, J=6.0 Hz, 2H), 2.40-2.24 (m, 4H),1.67-1.58 (m, 4H).

EXAMPLE 396-acetyl-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-one

To a suspension of the compound prepared in Example 11(1) (150 mg) intetrahydrofuran (2.9 mL) was added an aqueous solution (1.1 mL) ofpotassium carbonate (157 mg) and then thereto was added acetyl chloride(0.05 mL) at 0° C., and the mixture was stirred at room temperature for4 hours. The reaction mixture was diluted with water and 1N hydrochloricacid was added thereto. The mixture was extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was washed with ether to give thecompound of the present invention (131 mg) having the following physicaldata.

TLC: Rf 0.36 (chloroform:methanol=8:1);

NMR (DMSO-d₆): δ 13.08 (s, 1H), 7.60-7.40 (m, 5H), 4.28 (s, 2H), 3.66(t, J=5.7 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 2.04 (s, 3H).

EXAMPLE 39(1)6-(2-(N,N-dimethylamino)acetyl)-4-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyridazin-1(2H)-onehydrochloride

By the same procedure as described in Example 39 and then by convertingto a corresponding salt by conventional method, using2-dimethylaminoacetyl chloride instead of acetyl chloride, the compoundof the present invention having the following physical data wasobtained.

TLC: Rf 0.57 (chloroform:methanol=4:1);

NMR (DMSO-d₆): δ 13.17 (s, 1H), 9.75 (brs, 1H), 7.64-7.36 (m, 5H),4.48-4.30 (m, 3H), 4.21 (m, 1H), 3.96-3.52 (m, 8H), 2.86-2.64 (m, 2H).

EXAMPLE 404-(N-(2-carboxyethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

By the same procedure as described in Reference example 11 using thecompound prepared in Example 23(36) instead of the compound prepared inExample 15, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.26 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.15 (m, 1H), 4.11 (m, 1H), 3.39 (s,2H), 3.23 (q, J=6.0 Hz, 2H), 2.58-2.35 (m, 2H), 2.42-2.32 (m, 4H),1.66-1.58 (m, 4H).

EXAMPLE 414-(N-(2-(4-hydroxyphenyl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

By the same procedure as described in Example 20 using the compoundprepared in Example 24(41) instead of the compound prepared in Example4(4), the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.35 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 9.15 (s, 1H), 8.04 (t, J=5.7 Hz, 1H),6.96 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.36 (s, 2H), 3.22 (m,2H), 2.58 (t, J=7.5 Hz, 2H), 2.33 (m, 4H), 1.61 (brs, 4H).

REFERENCE EXAMPLE 18 3-hydroxy-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one

To a solution of 3,4,5,6-tetrahydrophthalic acid anhydride (10.0 g) intetrahydrofuran (50.0 mL) was added sodium borohydride (600 mg) in icebath. The mixture was stirred at room temperature for 30 minutes andrefluxed for 5 hours. After cooling to room temperature, 1N hydrochloricacid (10.0 mL) was added to the reaction mixture, which wasconcentrated. Water was added to the residue, which was extracted withethyl acetate. The extract was washed with water and brine sequentially,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel (ethylacetate:hexane=1:4) to give the title compound (5.40 g) having thefollowing physical data.

TLC: Rf 0.64 (ethyl acetate:hexane=1:1);

NMR (CDCl₃): δ 5.98 (brs, 1H), 4.90-4.50 (m, 1H), 2.52-2.40 (m, 1H),2.32-2.16 (m, 3H), 1.86-1.60 (m, 4H).

REFERENCE EXAMPLE 19Tributyl(3-oxo-1,3,4,5,6,7-hexahydro-2-benzofuran-1-yl)phosphoniumbromide

A mixed solution of the compound prepared in Reference example 18 (1.54g), tri-n-butylphosphine (2.02 g) and hydrogen bromide acetic acidsolution (47%, 1.20 mL) in acetic acid (0.700 mL) was refluxed for 21hours. After cooling to room temperature, the reaction mixture wasconcentrated. The residue was purified by column chromatography onsilica gel (methylene chloride:methanol=20:1) to give the title compound(3.56 g) having the following physical data.

TLC: Rf 0.51 (methanol:methylene chloride=1:10).

REFERENCE EXAMPLE 203-benzylidene-4,5,6,7-tetrahydro-2-benzofuran-1(3H)-one

To a solution of the compound prepared in Reference example 19 (419 mg)and benzaldehyde (106 mg) in methylene chloride (4.00 mL) was addedtriethylamine (0.130 mL) and the mixture was stirred at room temperaturefor 3 hours. Water was added to the reaction mixture, which wasextracted with ethyl acetate. The extract was washed with water andbrine sequentially, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane=1:8) to give the title compound (206mg) having the following physical data.

TLC: Rf 0.83 (hexane:ethyl acetate=2:1).

EXAMPLE 42 4-benzyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one

A solution of the compound prepared in Reference example 20 (206 mg) andhydrazine monohydrate (49.0 μL) in ethanol (4.00 mL) was refluxed for 1hour. Hydrazine monohydrate (49.0 μL) was added to the reaction mixture,which was refluxed for 1 hour. After cooling the reaction mixture toroom temperature, the deposited crystal was collected by filtration. Itwas washed with ethanol and hexane, and dried under reduced pressure togive the compound of the present invention (152 mg) having the followingphysical data.

TLC: Rf 0.63 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 7.32-7.24 (m, 2H), 7.23-7.13 (m, 3H),3.88 (s, 2H), 2.44-2.25 (m, 4H), 1.65-1.54 (m, 4H).

EXAMPLE 43 TO EXAMPLE 43(6)

By the same procedure as described in Reference example 20→Example 42using a corresponding derivative instead of benzaldehyde, the followingcompounds of the present invention were obtained.

EXAMPLE 43 4-(2-phenylethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.51 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.54 (s, 1H), 7.35-7.15 (m, 5H), 2.90-2.82 (m, 2H),2.81-2.72 (m, 2H), 2.52-2.42 (m, 2H), 2.41-2.32 (m, 2H), 1.70-1.58 (m,4H).

EXAMPLE 43(1)4-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.42 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.59 (s, 1H), 8.45-8.39 (m, 2H), 7.56 (m, 1H), 7.31(dd, J=7.5, 4.8 Hz, 1H), 3.92 (s, 2H), 2.46-2.33 (m, 4H), 1.72-1.56 (m,4H).

EXAMPLE 43(2)4-(pyridin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.59 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 8.45 (d, J=4.5 Hz, 1H), 7.71 (t, J=7.8Hz, 1H), 7.28-7.18 (m, 2H), 4.04 (s, 2H), 2.44-2.32 (m, 4H), 1.68-1.56(m, 4H).

EXAMPLE 43(3)4-(5-methylfuran-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.68 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 5.95 (m, 2H), 3.84 (s, 2H), 2.50-2.35(m, 4H), 2.18 (s, 3H), 1.70-1.58 (m, 4H).

EXAMPLE 43(4) 4-(2-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.59 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.40 (s, 1H), 8.03 (dd, J=7.8, 1.2 Hz, 1H), 7.68 (dt,J=1.2, 7.8 Hz, 1H), 7.53 (m, 1H), 7.46 (d, J=7.8 Hz, 1H), 4.24 (s, 2H),2.56-2.46 (m, 2H), 2.44-2.35 (m, 2H), 1.78-1.62 (m, 4H).

EXAMPLE 43(5) 4-(3-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

NMR (DMSO-d₆): δ 12.61 (s, 1H), 8.15-8.06 (m, 2H), 7.68-7.57 (m, 2H),4.06 (s, 2H), 2.47-2.34 (m, 4H), 1.70-1.56 (m, 4H).

EXAMPLE 43(6) 4-(4-nitrobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.60 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.65 (s, 1H), 8.16 (dt, J=6.9, 1.8 Hz, 2H), 7.46 (dt,J=6.9, 1.8 Hz, 2H), 4.05 (s, 2H), 2.42-2.33 (m, 4H), 1.70-1.55 (m, 4H).

EXAMPLE 44 4-(2-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

Under an atmosphere of hydrogen, a mixed solution of the compoundprepared in Example 43(4) (145 mg) and 10% palladium on carbon (30.0 mg)in methanol (15.0 mL) was stirred at room temperature for 30 minutes.The reaction mixture was filtrated through Celite. The filtrate wasconcentrated to give the compound of the present invention (129 mg)having the following physical data.

TLC: Rf 0.42 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 6.91 (dt, J=1.2, 7.8 Hz, 1H), 6.72 (dd,J=7.8, 1.2 Hz, 1H), 6.61 (dd, J=7.8, 1.2 Hz, 1H), 6.46 (dt, J=1.2, 7.8Hz, 1H), 4.97 (s, 2H), 3.66 (s, 2H), 2.50-2.30 (m, 4H), 1.70-1.57 (m,4H).

EXAMPLE 44(1) TO EXAMPLE 44(2)

By the same procedure as described in Example 44 using the compoundprepared in Example 43(5) or 43(6) instead of the compound prepared inExample 43(4), the following compounds of the present invention wereobtained.

EXAMPLE 44(1) 4-(3-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneFree Form:

TLC: Rf 0.38 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 6.91 (t, J=8.1 Hz, 1H), 6.37 (d, J=8.1Hz, 1H), 6.31 (s, 1H), 6.29 (d, J=8.1 Hz, 1H), 5.00 (s, 2H), 3.71 (s,2H), 2.45-2.30 (m, 4H), 1.70-1.50 (m, 4H).

Methanesulfonate:

TLC: Rf 0.53 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.67 (s, 1H), 9.60 (br, 3H), 7.41 (t, J=7.8 Hz, 1H),7.22 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 3.93 (s,2H), 2.43-2.28 (m, 4H), 2.33 (s, 3H), 1.67-1.54 (m, 4H).

EXAMPLE 44(2) 4-(4-aminobenzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.44 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.55 (s, 1H), 6.78 (d, J=8.1 Hz, 2H), 6.47 (d, J=8.1Hz, 2H), 4.90 (s, 2H), 3.68 (s, 2H), 2.42-2.25 (m, 4H), 1.70-1.50 (m,4H).

EXAMPLE 45 4-phenyl-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-1-one

A solution of(4aS,7aR)-4-phenyl-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[d]pyridazin-1-one(210 mg; It was prepared by the same procedure as described in Example 1using (1R,2S)-2-benzoylcyclopentanecarboxylic acid instead of thecompound prepared in Reference example 1.) and thionyl chloride (0.500mL) in benzene (3.00 mL) was refluxed for 18 hours. After cooling toroom temperature, the reaction mixture was concentrated. The residue wasrecrystallized from ethyl acetate to give the compound of the presentinvention (154 mg) having the following physical data.

TLC: Rf 0.21 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 13.02 (s, 1H), 7.62-7.58 (m, 2H), 7.50-7.42 (m, 3H),2.99 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.06-1.96 (m, 2H).

REFERENCE EXAMPLE 21 6-phenyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

To a solution of 2,3-pyridinedicarboxylic acid anhydride (19.4 g) intetrahydrofuran (260 mL) was added aniline (11.8 mL) and the mixture wasrefluxed 2 hours. The reaction mixture was concentrated. Aceticanhydride (65 mL) was added to the reaction mixture, which was refluxedfor 1.5 hours. After cooling in ice bath, the reaction mixture waspoured in ice water (200 mL) and stirred for 1 hours. The precipitatewas collected by filtration. It was washed with water and then washedwith ethanol on heating to give the title compound (20.9 g) having thefollowing physical data.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 7.48 (m, 5H) 7.70 (dd, J=7.69, 4.94 Hz, 1H) 8.28 (dd,J=7.69, 1.65 Hz, 1H) 9.06 (dd, J=4.94, 1.65 Hz, 1H).

REFERENCE EXAMPLE 227-(3-aminophenyl)-7-hydroxy-6-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of 3-(bis(trimethylsilyl)amino)phenylmagnesium chloride intetrahydrofuran (5.50 mL, 1.0M) was added dropwise to a suspension ofthe compound prepared in Reference example 21 (1.12 g) intetrahydrofuran (20 mL) in ice bath and the mixture was stirred for 1hour. 1N hydrochloric acid (10 mL) was added dropwise to the reactionmixture, which was stirred for 30 minutes. A saturated aqueous sodiumhydrogen carbonate solution (10 mL) was added to the reaction mixture,which was extracted with ethyl acetate. The extract was washed withbrine, dried over anhydrous sodium sulfate and concentrated. The residuewas washed with ethyl acetate on heating to give the title compound(1.35 g) having the following physical data.

TLC: Rf 0.52 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 5.02 (s, 2H) 6.36 (m, 1H) 6.47 (m, 1H) 6.62 (t, J=1.92Hz, 1H) 6.86 (t, J=7.83 Hz, 1H) 7.14 (m, 1H) 7.28 (m, 2H) 7.54 (m, 4H)8.20 (dd, J=7.69, 1.65 Hz, 1H) 8.70 (dd, J=4.94, 1.65 Hz, 1H).

REFERENCE EXAMPLE 23 2-(3-aminobenzoyl)nicotinic acid

To the compound prepared in Reference example 22 (3.17 g) was added 6Nhydrochloric acid (20 mL) and the mixture was refluxed overnight. Thereaction mixture was cooled in ice bath, adjusted to pH 5 with 5N sodiumhydroxide solution (24 mL) and concentrated. The residue was azeotropedwith ethanol and suspended in ethanol (50 mL) with refluxing.Unnecessary sodium chloride was separated by filtration. The filtratewas concentrated. The residue was washed with isopropanol (15 mL) onheating to give the title compound (2.13 g) having the followingphysical data.

TLC: Rf 0.49 (methylene chloride:methanol:acetic acid=8:1:1);

NMR (DMSO-d₆): δ 6.74 (m, 2H) 6.85 (t, J=2.00 Hz, 1H) 7.09 (t, J=7.87Hz, 1H) 7.63 (dd, J=7.97, 4.76 Hz, 1H) 8.33 (dd, J=7.97, 1.55 Hz, 1H)8.77 (dd, J=4.76, 1.55 Hz, 1H).

REFERENCE EXAMPLE 24 8-(3-aminophenyl)pyrido[2,3-d]pyridazin-5(6H)-one

To a suspension of the compound prepared in Reference example 23 (1.94g) in ethanol (40 mL) was added hydrazine monohydrate (400 mg) and themixture was refluxed overnight. After cooling the reaction mixture toroom temperature, the precipitate was collected by filtration. It waswashed with ethanol to give the title compound (1.70 g) having thefollowing physical data.

TLC: Rf 0.54 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 5.14 (s, 2H) 6.64 (m, 1H) 6.94 (m, 1H) 6.99 (m, 1H)7.09 (t, J=7.69 Hz, 1H) 7.84 (dd, J=8.06, 4.39 Hz, 1H) 8.63 (dd, J=8.06,1.83 Hz, 1H) 9.12 (dd, J=4.39, 1.83 Hz, 1H) 13.00 (s, 1H).

EXAMPLE 468-(3-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

To a suspension of the compound prepared in Reference example 24 (1.67g) and platinum oxide (83 mg) in dimethylformamide (35 mL) was added 6Nhydrochloric acid (2.5 mL) and the mixture was stirred 8 hours under anatmosphere of hydrogen. The reaction mixture was filtrated throughCelite. The filtrate was concentrated. A saturated aqueous sodiumhydrogen carbonate solution was added to the residue, which wasextracted with tetrahydrofuran three times. The combined organic layerwas washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was dissolved in methanol (35 mL) on heating.Activated carbon (340 mg) was added to the mixture, which was stirredfor 15 minutes. Activated carbon was filtrated through Celite. Thefiltrate was concentrated. The residue was washed with isopropanol onheating to give the compound of the present invention (1.25 g; freeform) having the following physical data. The obtained compound (242 mg)was suspended in methanol (4 mL). A solution of methanesulfonic acid (96mg) in methanol (1 mL) was added to the mixture, which was stirred. Thedeposited crystal was collected by filtration. It was washed withmethanol to give the compound of the present invention (258 mg;methanesulfonate) having the following physical data.

Free Form:

TLC: Rf 0.40 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.00 (s, 1H), 7.07 (m, 1H), 6.64-6.60 (m, 2H), 6.53(d, J=7.3 Hz, 1H), 5.60 (s, 1H), 5.21 (s, 2H), 3.15 (m, 2H), 2.38 (t,J=6.2 Hz, 2H), 1.71 (m, 2H).

Methanesulfonate:

TLC: Rf 0.40 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.28 (s, 1H), 7.53 (m, 1H), 7.40-7.30 (m, 3H) 3.13 (m,2H), 2.40 (t, J=6.0 Hz, 2H), 2.35 (s, 3H), 1.73 (m, 2H).

EXAMPLE 47 TO EXAMPLE 47(13)

By the same procedure as described in Reference example 21→Referenceexample 22→Reference example 23→Reference example 24→Example 46, ifnecessary, by converting to corresponding salts by conventional method,using furo[3,4-b]pyridine-5,7-dione or a corresponding derivative, and acorresponding derivative instead of3-(bis(trimethylsilyl)amino)phenylmagnesium chloride, the followingcompounds of the present invention were obtained.

EXAMPLE 478-(3-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.56 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.29 (s, 1H), 7.39 (t, J=8.1 Hz, 1H), 7.22-6.78 (m,3H), 3.15 (m, 2H), 3.01 (s, 6H), 2.41 (t, J=6.0 Hz, 2H), 2.33 (s, 3H),1.73 (m, 2H).

EXAMPLE 47(1)8-benzyl-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.51 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.13 (s, 1H), 7.31-7.16 (m, 5H), 6.22 (brs, 2H), 3.83(s, 2H), 3.19 (t, J=6.0 Hz, 2H), 2.36 (t, J=6.0 Hz, 2H), 2.32 (s, 3H),1.73-1.65 (m, 2H).

EXAMPLE 47(2)8-(3-methoxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.50 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.27 (s, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.03-6.96 (m,3H), 6.21 (m, 2H), 3.78 (s, 3H), 3.16-3.13 (m, 2H), 2.41 (t, J=6.0 Hz,2H), 2.32 (s, 3H), 1.76-1.71 (m, 2H).

EXAMPLE 47(3)8-(4-aminophenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.25 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 12.2 (brs, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.16 (d, J=8.1Hz, 2H), 3.14 (m, 2H), 2.40 (t, J=6.3 Hz, 2H), 2.33 (s, 3H), 1.73 (m,2H).

EXAMPLE 47(4)8-(3-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.49 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.21 (s, 1H), 9.79 (br-s, 1H), 7.80-7.37 (m, 4H), 5.83(s, 1H), 4.40 (d, J=4.0 Hz, 2H), 3.96 (d, J=12.1 Hz, 2H), 3.62 (t,J=11.7 Hz, 2H), 3.30 (d, J=12.1 Hz, 2H), 3.20-3.06 (m, 4H), 2.40 (t,J=6.0 Hz, 2H), 2.30 (s, 3H), 1.73 (m, 2H).

EXAMPLE 47(5)8-(4-(N,N-dimethylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.50 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.38 (s, 1H), 7.34 (d, J=8.1 Hz, 2H), 6.95 (m, 2H),3.15 (m, 2H), 2.99 (s, 6H), 2.42 (m, 2H), 2.34 (s, 3H), 1.73 (m, 2H).

EXAMPLE 47(6)8-(4-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onedimethanesulfonate

TLC: Rf 0.51 (methylene chloride:methanol=10:1);

NMR (CD₃OD): δ 7.72 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 4.46 (s,2H), 4.11-4.02 (m, 2H), 3.80 (t, J=12.6 Hz, 2H), 3.42 (d, J=12.6 Hz,2H), 3.40-3.18 (m, 4H), 2.69 (s, 6H), 2.72-2.64 (m, 2H), 2.00-1.89 (m,2H).

EXAMPLE 47(7)8-(2-(morpholin-4-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.54 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.32 (s, 1H), 9.45 (br, 1H), 7.76 (m, 1H), 7.64-7.53(m, 2H), 7.43 (m, 1H), 5.64 (br, 1H), 4.25 (s, 2H), 3.87 (d, J=12.0 Hz,2H), 3.67 (t, J=12.0 Hz, 2H), 3.25 (d, J=12.0 Hz, 2H), 3.16-3.00 (m,4H), 2.42 (t, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.79-1.66 (m, 2H).

EXAMPLE 47(8)8-(3-(4-ethylpiperazin-1-ylmethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onetrihydrochloride

TLC: Rf 0.42 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.40 (br, 1H), 11.99 (br, 1H), 7.77-7.69 (m, 2H),7.62-7.48 (m, 2H), 6.30-5.30 (br, 3H), 4.45 (s, 2H), 3.80-3.50 (m, 4H),3.70-3.40 (m, 4H), 3.30-3.00 (m, 4H), 2.42 (t, J=6.3 Hz, 2H), 1.80-1.66(m, 2H), 1.24 (t, J=7.2 Hz, 3H).

EXAMPLE 47(9)8-(3-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.27 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.21 (s, 1H), 9.59 (br, 1H), 7.62-7.52 (m, 4H), 5.82(s, 1H), 4.35-4.31 (m, 2H), 3.20-3.12 (m, 2H), 2.76 (s, 3H), 2.75 (s,3H), 2.41 (t, J=6.3 Hz, 2H), 2.30 (s, 3H), 1.81-1.68 (m, 2H).

EXAMPLE 47(10)8-(4-(N,N-dimethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.82 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.19 (s, 1H), 9.68 (br, 1H), 7.57 (d, J=8.4 Hz, 2H),7.53 (d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.34 (s, 2H), 3.18-3.10 (m, 2H),2.76 (s, 6H), 2.40 (t, J=6.0 Hz, 2H), 2.31 (s, 3H), 1.80-1.68 (m, 2H).

EXAMPLE 47(11)8-(4-(N,N-diethylaminomethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.38 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.20 (s, 1H), 9.34 (br, 1H), 7.60 (d, J=8.4 Hz, 2H),7.54 (d, J=8.4 Hz, 2H), 5.77 (s, 1H), 4.36 (d, J=4.8 Hz, 2H), 3.12-3.02(m, 6H), 2.40 (t, J=6.0 Hz, 2H), 2.30 (s, 3H), 1.80-1.68 (m, 2H), 1.24(t, J=7.2 Hz, 6H).

EXAMPLE 47(12)4-(4-(N,N-dimethylaminomethyl)phenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.49 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.95 (s, 1H), 9.64 (br, 1H), 7.60-7.52 (m, 4H), 4.33(s, 2H), 2.76 (s, 6H), 2.50-2.40 (m, 2H), 2.40-2.32 (m, 2H), 2.30 (s,3H), 1.76-1.66 (m, 2H), 1.66-1.55 (m, 2H).

EXAMPLE 47(13)8-(4-(2-(N,N-dimethylamino)ethyl)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.50 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.12 (s, 1H), 9.41 (br, 1H), 7.42 (d, J=8.1 Hz, 2H),7.37 (d, J=8.1 Hz, 2H), 5.70 (s, 1H), 3.35-3.25 (m, 2H), 3.18-3.09 (m,2H), 3.05-2.96 (m, 2H), 2.83 (s, 6H), 2.39 (t, J=6.3 Hz, 2H), 2.30 (s,3H), 1.80-1.68 (m, 2H).

REFERENCE EXAMPLE 25 2-(3-aminobenzoyl)nicotinic acid methyl ester

After cooling methanol (5 mL) to −15° C., thionyl chloride (1.3 mL) wasadded dropwise thereto and the solution was stirred for 15 minutes. Tothe solution was added the compound prepared in Reference example 23(1.21 g). The solution was allowed to return to room temperature andthen refluxed overnight. The reaction mixture was concentrated. To theresidue were added a saturated aqueous sodium hydrogen carbonatesolution and ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate and concentrated. The residue wasrecrystallized from isopropanol (5 mL) to give the title compound (815mg) having the following physical data.

TLC: Rf 0.37 (hexane:ethyl acetate=1:3);

NMR (DMSO-d₆): δ 3.69 (s, 3H) 5.36 (s, 2H) 6.79 (m, 2H) 6.89 (m, 1H)7.12 (t, J=7.83 Hz, 1H) 7.70 (dd, J=8.04, 4.81 Hz, 1H) 8.39 (dd, J=8.04,1.65 Hz, 1H) 8.83 (dd, J=4.74, 1.65 Hz, 1H).

REFERENCE EXAMPLE 26 2-(3-(trifluoroacetyl)aminobenzoyl)nicotinic acidmethyl ester

To a solution of the compound prepared in Reference example 25 (800 mg)in methylene chloride (15 mL) were added pyridine (505 μL) andtrifluoroacetic acid anhydride (529 μL) sequentially in ice bath, andthe mixture was stirred for 30 minutes. The reaction mixture was dilutedwith methylene chloride and washed with 1N hydrochloric acid and watersequentially. The organic layer was dried over anhydrous sodium sulfateand concentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:1) to give the title compound (1.10g) having the following physical data.

TLC: Rf 0.48 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.79 (s, 3H) 7.49 (t, J=7.97 Hz, 1H) 7.56 (dd, J=8.11,4.81 Hz, 1H) 7.63 (m, 1H) 7.99 (m, 2H) 8.28 (s, 1H) 8.39 (dd, J=8.11,1.65 Hz, 1H) 8.82 (dd, J=4.81, 1.65 Hz, 1H).

REFERENCE EXAMPLE 272-(3-(N-methyl-N-(trifluoroacetyl)amino)benzoyl)nicotinic acid methylester

To a solution of the compound prepared in Reference example 26 (1.06 g)in dimethylformamide (12 mL) was added sodium hydride (127 mg) in icebath and the mixture was stirred for 30 minutes. Methyl iodide (224 μL)was added to the reaction mixture, which was stirred at 0° C. for 1 hourand subsequently at room temperature for 6 hours. The reaction mixturewas poured in ice water and extracted with a mixed solvent (ethylacetate:hexane=1:1) twice. The combined organic layer was washed withwater and brine sequentially, dried over anhydrous sodium sulfate andconcentrated. The residue was recrystallized from a mixed solvent(isopropanol:hexane=1:1) to give the title compound (892 mg) having thefollowing physical data.

TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 3.37 (s, 3H) 3.76 (s, 3H) 7.55 (m, 3H) 7.71 (s, 1H) 7.87(d, J=7.69 Hz, 1H) 8.40 (dd, J=7.97, 1.65 Hz, 1H) 8.83 (dd, J=4.94, 1.65Hz, 1H).

REFERENCE EXAMPLE 288-(3-(N-methylamino)phenyl)pyrido[2,3-d]pyridazin-5(6H)-one

To a solution of the compound prepared in Reference example 27 (880 mg)in ethanol (12 mL) was added a solution of hydrazine monohydrate (240mg) in ethanol (3 mL) and the mixture was refluxed overnight. 1N sodiumhydroxide solution (5 mL) was added to the reaction mixture, which wasrefluxed for 1 hour. The reaction mixture was cooled in ice bath and 1Nhydrochloric acid (5 mL) was added thereto. The precipitate wascollected by filtration. It was washed with water and then washed withethanol on heating to give the title compound (581 mg) having thefollowing physical data.

TLC: Rf 0.39 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 2.69 (d, J=5.13 Hz, 3H) 5.73 (q, J=5.13 Hz, 1H) 6.62(m, 1H) 6.97 (m, 2H) 7.18 (t, J=7.69 Hz, 1H) 7.85 (dd, J=8.06, 4.39 Hz,1H) 8.64 (dd, J=8.06, 1.83 Hz, 1H) 9.13 (dd, J=4.39, 1.83 Hz, 1H) 13.02(s, 1H).

EXAMPLE 488-(3-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

By the same procedure as described in Example 46 using the compoundprepared in Reference example 28 instead of the compound prepared inReference example 24, the compounds of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.49 (methylene chloride:methanol=9:1);

NMR (DMSO-d₆): δ 12.31 (s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.18-6.85 (m,3H), 3.16 (m, 2H), 2.83 (s, 3H), 2.41 (t, J=6.0 Hz, 2H), 2.34 (s, 3H),1.73 (m, 2H).

EXAMPLE 498-(4-(N-methylamino)phenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

By the same procedure as described in Reference example 25→Referenceexample 26→Reference example 27→Reference example 28→Example 46 using acorresponding derivative instead of the compound prepared in Referenceexample 23, the compounds of the present invention having the followingphysical data was obtained.

TLC: Rf 0.39 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.26 (brs, 1H), 7.27 (d, J=7.8 Hz, 2H), 6.79 (d, J=7.8Hz, 2H), 5.96 (brs, 3H), 3.16 (m, 2H), 2.76 (s, 3H), 2.41 (m, 2H), 2.32(s, 3H), 1.72 (m, 2H).

EXAMPLE 50 TO EXAMPLE 50(4)

By the same procedure as described in Reference example 20→Example 42using a corresponding derivative instead of benzaldehyde, the compoundsof the present invention having the following physical data wasobtained.

EXAMPLE 50 4-(2-phenoxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.41 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 12.6 (s, 1H), 7.30-7.22 (m, 2H), 6.95-6.90 (m, 3H),4.26 (t, J=6.9 Hz, 2H), 2.97 (t, J=6.9 Hz, 2H), 2.60-2.35 (m, 4H), 1.66(m, 4H).

EXAMPLE 50(1) 4-(3-phenoxypropyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.40 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 12.52 (s, 1H), 7.26 (m, 2H), 6.90 (m, 3H), 4.01 (t,J=6.3 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H), 2.55-2.30 (m, 4H), 2.01 (m, 2H),1.64 (m, 4H).

EXAMPLE 50(2)4-(4-(3-(N,N-dimethylamino)propoxy)benzyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.37 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 9.32 (brs, 1H), 7.08 (d, J=8.4 Hz, 2H),6.86 (d, J=8.4 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 3.81 (s, 2H), 3.24-3.16(m, 2H), 2.79 (s, 6H), 2.40-2.28 (m, 4H), 2.14-2.02 (m, 2H), 1.64-1.54(m, 4H).

EXAMPLE 50(3)4-(2-benzyloxyethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.54 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 12.5 (s, 1H), 7.35-7.22 (m, 5H), 4.47 (s, 2H), 3.69 (t,J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.50-2.36 (m, 4H), 1.63 (m, 4H).

EXAMPLE 50(4)4-(quinolin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.53 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.60 (s, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.08 (d, J=1.8Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H), 7.70(ddd, J=8.1, 6.9, 1.5 Hz, 1H), 7.57 (ddd, J=8.1, 6.9, 1.5 Hz, 1H), 4.12(s, 2H), 2.54-2.40 (m, 2H), 2.46-2.30 (m, 2H), 1.70-1.55 (m, 4H).

EXAMPLE 51 TO EXAMPLE 51(3)

By the same procedure as described in Example 27, if necessary, byconverting to corresponding salts by conventional method, using acorresponding derivative instead of the compound prepared in Referenceexample 13 and a corresponding derivative instead of benzylamine, thefollowing compounds of the present invention were obtained.

EXAMPLE 514-(5-(piperidin-1-yl)pentyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

TLC: Rf 0.83 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.51 (s, 1H), 9.96 (br, 1H), 3.46-3.28 (m, 2H),3.02-2.84 (m, 2H), 2.95-2.65 (m, 2H), 2.54-2.44 (m, 2H), 2.42-2.32 (m,2H), 1.84-1.54 (m, 14H), 1.44-1.26 (m, 4H).

EXAMPLE 51(1)8-(2-(4-(2-(morpholin-4-yl)ethyl)piperazin-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyridazin-5(1H)-one

TLC: Rf 0.15 (methylene chloride:methanol:saturated aqueousammonia=4:1:0.5%);

NMR (CD₃OD): δ 3.69 (m, 4H), 3.33 (m, 2H), 2.78-2.42 (m, 22H), 1.85 (m,2H).

EXAMPLE 51(2)8-(2-(4-benzyloxycarbonyl-1,4-diazepan-1-yl)ethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.19 (methylene chloride:methanol=19:1);

NMR (DMSO-d₆): δ 11.97 (s, 1H), 9.39 (s, 1H), 7.41-7.30 (m, 5H), 6.38(brs, 1H), 5.11 (s, 2H), 4.32 (brs, 2H), 3.87 (m, 1H), 3.70-3.40 (m,7H), 3.30-3.15 (m, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.35 (t, J=6.3 Hz, 2H),2.31 (s, 3H), 2.07 (m, 2H), 1.72 (m, 2H).

EXAMPLE 51(3)4-(4-(morpholin-4-yl)butyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneHydrochloride:

TLC: Rf 0.29 (methylene chloride:methanol=10:1);

NMR (300 MHz, CD₃OD) 3.10-3.00 (m, 4H), 2.37-2.26 (m, 4H), 2.25-2.16 (m,2H), 1.85 (t, J=6.9 Hz, 2H), 1.83-1.75 (m, 2H), 1.75-1.67 (m, 2H),1.08-0.88 (m, 8H).

Methanesulfonate:

TLC: Rf 0.25 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.55 (s, 1H), 9.52 (br, 1H), 4.01-3.92 (m, 2H), 3.64(t, J=11.4 Hz, 2H), 3.45-3.36 (m, 2H), 3.17-2.95 (m, 4H), 2.58-2.43 (m,4H), 2.43-2.34 (m, 2H), 2.31 (s, 3H), 1.77-1.54 (m, 8H).

EXAMPLE 52 TO EXAMPLE 52(3)

By the same procedure as described in Example 24, if necessary, byconverting to corresponding salts by conventional method, using acorresponding ester derivative instead of the compound prepared inExample 15 and a corresponding derivative instead of 2-aminoethanol, thefollowing compounds of the present invention were obtained.

EXAMPLE 528-(N-(4-hydroxybutyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyridazin-5(1H)-one

TLC: Rf 0.54 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.84 (s, 1H), 8.06 (t, J=5.7 Hz, 1H), 6.42 (s, 1H),4.37 (t, J=4.8 Hz, 1H), 3.35 (m, 4H), 3.18 (m, 2H), 3.03 (td, J=6.6, 5.7Hz, 2H), 2.32 (t, J=6.3 Hz, 2H), 1.69 (m, 2H), 1.41 (m, 4H).

EXAMPLE 52(1)8-(N-(4-(morpholin-4-yl)butyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyridazin-5(1H)-one

TLC: Rf 0.22 (methanol:methylene chloride=1:4);

NMR (DMSO-d₆): δ 11.84 (s, 1H), 8.06 (t, J=5.4 Hz, 1H), 6.43 (s, 1H),3.55-3.52 (m, 4H), 3.32-3.31 (m, 2H), 3.18 (brs, 2H), 3.04 (m, 2H),2.34-2.19 (m, 8H), 1.71-1.68 (m, 2H), 1.40-1.36 (m, 4H).

EXAMPLE 52(2)8-(N-(2-(azepan-1-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3,d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.39 (methanol:methylene chloride:saturated aqueousammonia=2:8:0.1);

NMR (DMSO-d₆): δ 11.90 (s, 1H), 9.13 (brs, 1H), 8.30 (t, J=5.4 Hz, 1H),6.30 (brs, 1H), 3.45-3.35 (m, 6H), 3.19-3.08 (m, 6H), 2.40-2.29 (m, 2H),2.33 (s, 3H), 1.80-1.52 (m, 10H).

EXAMPLE 52(3)4-(N-(6-hydroxyhexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.23 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.56 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 4.32 (t, J=5.1Hz, 1H), 3.38 (s, 2H), 3.37-3.33 (m, 2H), 3.05-2.99 (m, 2H), 2.41-2.36(m, 4H), 1.63 (m, 4H), 1.40-1.23 (m, 8H).

EXAMPLE 53 TO EXAMPLE 53(1)

By the same procedure as described in Example 34 using a correspondingderivative instead of the compound prepared in Example 33, the followingcompounds of the present invention were obtained.

EXAMPLE 534-(N-(5-bromopentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.53 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 8.02 (t, J=5.1 Hz, 1H), 3.51 (t, J=6.3Hz, 2H), 3.39 (s, 2H), 3.04 (q, J=6.3 Hz, 2H), 2.46-2.33 (m, 4H), 1.78(quin, J=6.3 Hz, 2H), 1.70-1.58 (m, 4H), 1.48-1.30 (m, 4H).

EXAMPLE 53(1)4-(N-(6-bromohexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.37 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 7.99 (t, J=5.4 Hz, 1H), 3.51 (t, J=6.6Hz, 2H), 3.38 (s, 2H), 3.06-3.00 (m, 2H), 2.41-2.36 (m, 4H), 1.82-1.75(m, 2H), 1.64 (m, 4H), 1.41-1.16 (m, 6H).

EXAMPLE 54 TO EXAMPLE 54(2)

By the same procedure as described in Example 28, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 53, 23(23) or 53(1) instead of the compoundprepared in Example 25(1), the following compounds of the presentinvention were obtained.

EXAMPLE 544-(N-(5-(morpholin-4-yl)pentyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

TLC: Rf 0.57 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.57 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 3.54 (t, J=4.8Hz, 4H), 3.38 (s, 2H), 3.02 (q, J=6.9 Hz, 2H), 2.46-2.33 (m, 4H),2.33-2.25 (m, 4H), 2.21 (t, J=6.9 Hz, 2H), 1.68-1.58 (m, 4H), 1.39(quin, J=6.9 Hz, 4H), 1.31-1.19 (m, 2H).

EXAMPLE 54(1)4-(N-(2-(azocan-1-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.67 (methanol:methylene chloride:28% ammonia water=2:8:0.1);

NMR (DMSO-d₆): δ 12.63 (s, 1H), 9.37 (brs, 1H), 8.36 (t, J=5.7 Hz, 1H),3.46 (s, 2H), 3.43-3.34 (m, 4H), 3.16-3.12 (m, 4H), 2.42-2.37 (m, 4H),2.29 (s, 3H), 1.84-1.49 (m, 14H).

EXAMPLE 54(2)4-(N-(6-(morpholin-4-yl)hexyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.22 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 12.58 (s, 1H), 9.48 (brs, 1H), 8.03 (t, J=5.4 Hz, 1H),3.98-3.94 (m, 2H), 3.67-3.39 (m, 6H), 3.07-3.01 (m, 6H), 2.48-2.36 (m,7H), 1.63-1.27 (m, 12H).

EXAMPLE 55 TO EXAMPLE 55(2)

By the same procedure as described in Reference example 22→Referenceexample 24→Example 20→Example 46, if necessary, by converting tocorresponding salts by conventional method, using a correspondingderivative instead of 4-(bis(trimethylsilyl)amino)phenylmagnesiumbromide, the following compounds of the present invention were obtained.

EXAMPLE 558-(3,4-dihydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.59 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 11.94 (s, 1H), 9.14 (br, 2H), 6.80 (s, 1H), 6.79 (d,J=7.8 Hz, 1H), 6.68 (m, 1H), 5.65 (s, 1H), 3.16-3.08 (m, 2H), 2.37 (t,J=6.0 Hz, 2H), 1.77-1.65 (m, 2H).

EXAMPLE 55(1)8-(4-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate

TLC: Rf 0.29 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 12.40 (brs, 1H), 9.20 (brs, 1H), 7.26 (d, J=8.7 Hz,2H), 6.84 (d, J=8.7 Hz, 2H), 3.16 (t, J=5.1 Hz, 2H), 2.42 (t, J=6.0 Hz,2H), 2.34 (s, 3H), 1.71 (m, 2H).

EXAMPLE 55(2)8-(2-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.4 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.58 (br, 1H), 9.58 (br, 1H), 7.29 (t, J=7.5 Hz, 1H),7.12 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.88 (t, J=7.5 Hz, 1H),5.96 (br, 1H), 3.23-3.12 (m, 2H), 2.54-2.4- (m, 2H), 1.82-1.64 (m, 2H).

EXAMPLE 56 TO EXAMPLE 56(6)

By the same procedure as described in Example 46, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 43(1), Example 43(2), 23(17), 23(22),24(11) or 24(16), or4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one instead ofthe compound prepared in Reference example 24 and, the followingcompounds of the present invention were obtained.

EXAMPLE 564-(piperidin-3-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one acetate

TLC: Rf 0.21 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.49 (br, 1H), 2.97-2.84 (m, 2H), 2.53-2.42 (m, 5H),2.41-2.31 (m, 4H), 2.26 (m, 1H), 1.84 (m, 1H), 1.82 (s, 3H), 1.77-1.53(m, 6H), 1.40 (m, 1H), 1.09 (m, 1H).

EXAMPLE 56(1)4-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one acetate

TLC: Rf 0.16 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d): δ 12.51 (br, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 2.58-2.40(m, 7H), 2.40-2.32 (m, 2H), 1.86 (s, 3H), 1.74-1.45 (m, 7H), 1.38-1.20(m, 2H), 1.10 (m, 1H).

EXAMPLE 56(2)4-(piperidin-2-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one acetate

TLC: Rf 0.58 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 12.47 (br, 1H), 3.01-2.91 (m, 2H), 2.56-2.42 (m, 6H),2.41-2.32 (m, 4H), 1.81 (s, 3H), 1.80 (m, 1H), 1.70-1.55 (m, 6H),1.22-1.07 (m, 2H).

EXAMPLE 56(3)4-(N-(piperidin-2-yl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.27 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.64 (s, 1H), 9.22 (d, J=7.5 Hz, 1H), 8.77 (br, 2H),4.83 (m, 1H), 3.55 (s, 2H), 3.10 (m, 1H), 2.97 (m, 1H), 2.55-2.35 (m,4H), 2.34 (s, 3H), 1.94-1.50 (m, 10H).

EXAMPLE 56(4)4-(N-(piperidin-2-ylmethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.55 (methylene chloride:methanol:28% ammonia water=15:5:1);

NMR (DMSO-d₆): δ 12.62 (s, 1H), 8.50 (m, 1H), 8.30-8.10 (m, 2H), 3.48(s, 2H), 3.40-3.00 (m, 4H), 2.84 (m, 1H), 2.46-2.34 (m, 4H), 2.32 (s,3H), 1.82-1.20 (m, 10H).

EXAMPLE 56(5)4-(N-(2-(piperidin-2-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.40 (methylene chloride:methanol:28% ammonia water=15:5:1);

NMR (DMSO-d₆): δ 12.61 (s, 1H), 8.41 (m, 1H), 8.30-8.16 (m, 2H), 3.42(s, 2H), 3.30-2.70 (m, 5H), 2.46-2.32 (m, 4H), 2.31 (s, 3H), 1.92-1.20(m, 12H).

EXAMPLE 56(6)4-(N-(2-(piperidin-3-yl)ethyl)carbamoylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onemethanesulfonate

TLC: Rf 0.28 (methylene chloride:methanol:28% ammonia water=15:5:1);

NMR (DMSO-d₆): δ 12.57 (brs, 1H), 8.26 (brs, 2H), 8.06 (t, J=5.5 Hz,1H), 3.39 (s, 2H), 3.24-3.02 (m, 4H), 2.73 (m, 1H), 2.46-2.32 (m, 4H),2.30 (s, 3H), 1.80-1.04 (m, 12H).

EXAMPLE 578-(3-hydroxyphenyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

By the same procedure as described in Example 20, if necessary, byconverting to corresponding salts by conventional method, using thecompound prepared in Example 47(2) instead of the compound prepared inExample 4(4), the compounds of the present invention having thefollowing data were obtained.

Free Form:

TLC: Rf 0.33 (methanol:methylene chloride=1:20);

NMR (DMSO-d₆): δ 12.06 (s, 1H), 9.60 (s, 1H), 7.25 (t, J=8.1 Hz, 1H),6.81 (m, 3H), 5.71 (s, 1H), 3.13 (m, 2H), 2.36 (m, 2H), 1.71 (m, 2H).

Sodium Salt:

TLC: Rf 0.43 (methanol:methylene chloride=1:9);

NMR (DMSO-d₆): δ 11.85 (brs, 1H), 6.92 (t, J=7.8 Hz, 1H), 6.36 (brs,2H), 6.17 (brs, 1H), 5.40 (s, 1H), 3.13 (m, 2H), 2.36 (m, 2H), 1.68 (m,2H).

EXAMPLE 588-(N-(2-(piperidin-4-yl)ethyl)carbamoylmethyl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

A mixed solution of the compound prepared in Example 24(44) (307 mg),10% palladium on carbon (307 mg) and ammonium formate (236 mg) inmethanol (3.00 mL) was refluxed for 30 minutes. After cooling to roomtemperature, the reaction mixture was filtrated through Celite. Thefiltrate was concentrated. The residue was washed with a mixed solutionof methanol and ethyl acetate and dried under reduced pressure to givethe compound of the present invention (187 mg) having the followingphysical data.

TLC: Rf 0.13 (methanol:methylene chloride:acetic acid=1:4:1);

NMR (DMSO-d₆): δ 11.83 (brs, 1H), 8.06 (t, J=5.1 Hz, 1H), 6.44 (s, 1H),3.18-2.09 (m, 13H), 1.69 (m, 2H), 1.52 (m, 2H), 1.29 (m, 3H), 0.94 (m,2H).

EXAMPLE 598-(pyridin-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one(compound A) and8-(piperidin-2-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one(compound B)

Under an atmosphere of argon, to8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one (118 mg; It wasprepared by the same procedure as described in Reference example22→Reference example 23→Reference example 24 using pyridin-2-ylmagnesiumbromide instead of 3-(bis(trimethylsilyl)amino)phenylmagnesiumchloride.) were added methanol (6 mL), methanesulfonate (51 mg) andplatinum oxide (12 mg) sequentially. Under an atmosphere of hydrogen,the reaction mixture was stirred at room temperature for 5.5 hours. Thereaction mixture was filtrated through Celite. The filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (methylene chloride:methanol=20:1 methylenechloride:methanol:water=8:2:0.2) to give free form of the compound A (14mg) and methanesulfonate of the compound B (77 mg) having the followingphysical data. The obtained compound A and B were converted tocorresponding salts or free form by conventional method to give thecompound of the present invention having the following physical data.

Free Form of the Compound A:

TLC: Rf 0.51 (methylene chloride:methanol=10:1).

NMR (DMSO-d₆): δ 12.39 (br, 1H), 8.88 (br, 1H), 8.59 (m, 1H), 8.04 (d,J=8.4 Hz, 1H), 7.93 (m, 1H), 7.44 (m, 1H), 3.40-3.25 (m, 2H), 2.43 (t,J=6.3 Hz, 2H), 1.85-1.74 (m, 2H).

Methanesulfonate of the Compound B:

TLC: Rf 0.15 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 12.36 (s, 1H), 8.76 (br, 2H), 6.63 (s, 1H), 4.21 (d,J=9.9 Hz, 1H), 3.30 (m, 1H), 3.28-3.16 (m, 2H), 2.89 (m, 1H), 2.36 (t,J=6.0 Hz, 2H), 2.29 (s, 3H), 2.03 (d, J=12.3 Hz, 1H), 1.84-1.60 (m, 6H),1.43 (m, 1H).

Free Form of the Compound B:

TLC: Rf 0.14 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 11.74 (s, 1H), 7.36 (s, 1H), 3.54 (dd, J=9.6, 3.9 Hz,1H), 3.26-3.16 (m, 2H), 2.94 (d, J=12.0 Hz, 1H), 2.65-2.50 (m, 1H), 2.32(t, J=6.3 Hz, 2H), 1.79 (m, 1H), 1.76-1.26 (m, 7H).

Methanesulfonate of the Compound A:

TLC: Rf 0.50 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.63 (br, 1H), 9.45 (br, 2H), 8.60 (d, J=4.5 Hz, 1H),8.06 (d, J=8.4 Hz, 1H), 7.97 (t, J=8.4 Hz, 1H), 7.48 (m, 1H), 3.40-3.33(m, 2H), 2.52-2.42 (m, 2H), 2.36 (s, 3H), 1.84-1.73 (m, 2H).

Dimethanesulfonate of the Compound B:

TLC: Rf 0.66 (methylene chloride:methanol:ammonia water=8:2:0.2);

NMR (DMSO-d₆): δ 1.45 (m, 1H) 1.72 (m, 6H) 2.04 (d, J=12.82 Hz, 1H) 2.37(m, 8H) 2.94 (s, 1H) 3.25 (m, 3H) 4.26 (t, J=10.44 Hz, 1H) 7.21 (m, 1H)8.71 (m, 1H) 8.89 (m, 1H) 12.48 (s, 1H).

EXAMPLE 59(1) TO EXAMPLE 59(3)

By the same procedure as described in Example 59, if necessary, byconverting to corresponding salts by conventional method, using8-(pyridin-3-yl)pyrido[2,3-d]pyridazin-5(6H)-one,8-(pyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one or8-(1-benzylpyridin-4-yl)pyrido[2,3-d]pyridazin-5(6H)-one instead of8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, the followingcompounds of the present invention were obtained.

EXAMPLE 59(1)8-(pyridin-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate (compound A) and8-(piperidin-3-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-oneacetate (compound B) Compound A:

TLC: Rf 0.66 (methylene chloride:methanol=4:1);

NMR (DMSO-d₆): δ 12.46 (s, 1H), 8.92 (s, 1H), 8.86 (d, J=5.1 Hz, 1H),8.37 (d, J=7.5 Hz, 1H), 7.91 (dd, J=7.5, 5.1 Hz, 1H), 6.20 (brs, 1H),3.13 (m, 2H), 2.41 (m, 2H), 2.31 (s, 3H), 1.75 (m, 2H).

Compound B:

TLC: Rf 0.12 (methylene chloride:methanol:acetic acid=4:1:2%);

NMR (DMSO-d₆): δ 11.75 (s, 1H), 6.48 (s, 1H), 3.18 (m, 2H), 2.98 (m,2H), 2.71 (m, 1H), 2.44 (m, 2H), 2.32 (m, 2H), 1.86 (s, 3H), 1.83 (m,1H), 1.74-1.43 (m, 5H).

EXAMPLE 59(2)8-(pyridin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-onemethanesulfonate (compound A) and8-(piperidin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one(compound B) Compound A:

TLC: Rf 0.28 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 12.63 (br, 1H), 8.90 (d, J=6.0 Hz, 2H), 8.00 (d, J=6.0Hz, 2H), 6.23 (br, 1H), 3.18-3.10 (m, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.31(s, 3H), 1.82-1.70 (m, 2H).

Free Form of Compound B:

TLC: Rf 0.053 (methylene chloride:methanol:acetic acid=4:1:2%);

NMR (DMSO-d₆): δ 11.71 (s, 1H), 6.33 (s, 1H), 3.16 (m, 2H), 2.94 (m,2H), 2.74-2.38 (m, 3H), 2.32 (m, 2H), 1.75-1.32 (m, 6H).

Dimethanesulfonate of Compound B:

TLC: Rf 0.86 (methylene chloride:methanol:water=8:2:0.2);

NMR (DMSO-d₆): δ 11.79 (br, 1H), 8.13 (br, 3H), 6.40 (s, 1H), 3.23-3.15(m, 2H), 3.15-3.04 (m, 2H), 2.81-2.64 (m, 3H), 2.33 (t, J=6.3 Hz, 2H),1.82 (s, 6H), 1.80-1.65 (m, 4H), 1.64-1.46 (m, 2H).

EXAMPLE 59(3)8-(1-cyclohexylmethylpiperidin-4-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

TLC: Rf 0.41 (methylene chloride:methanol:acetic acid=4:1:2%).

EXAMPLE 60 TO EXAMPLE 60(7)

By the same procedure as described in Reference example 2→Referenceexample 3→Example 3 using thiomorpholin-3-ylcarboxylic acid ethyl esteror a corresponding derivative, and a corresponding derivative instead of3-nitrobenzoyl chloride, the following compounds of the presentinvention were obtained.

EXAMPLE 604-cyclohexenyl-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.18 (hexane:ethyl acetate=2:1);

NMR (DMSO-d₆): δ 10.27 (s, 1H), 5.79 (m, 1H), 4.03 (dd, J=10.3, 3.0 Hz,1H), 3.82 (dt, J=13.8, 3.0 Hz, 1H), 3.06 (ddd, J=13.8, 11.7, 2.1 Hz,1H), 2.77 (m, 1H), 2.74-2.58 (m, 2H), 2.42 (m, 1H), 2.10-2.00 (m, 4H),1.68-1.50 (m, 4H).

EXAMPLE 60(1)4-(furan-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.37 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.66 (s, 1H) 7.80 (m, 1H), 6.72 (d, J=3.3 Hz, 1H),6.58 (m, 1H), 4.22 (dd, J=10.2, 3.0 Hz, 1H), 3.73 (dt, J=14.1, 3.0 Hz,1H), 3.22 (m, 1H), 2.94-2.72 (m, 3H), 2.49 (m, 1H).

EXAMPLE 60(2)4-(thiophen-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.37 (hexane:ethyl acetate=1:1);

NMR (DMSO-d₆): δ 10.62 (s, 1H), 7.65 (dd, J=5.1, 1.2 Hz, 1H), 7.30 (dd,J=3.6, 1.2 Hz, 1H), 7.11 (dd, J=5.1, 3.6 Hz, 1H), 4.24 (dd, J=8.1, 3.3Hz, 1H), 3.96 (dt, J=13.8, 3.3 z, 1H), 3.20 (m, 1H), 2.92-2.76 (m, 3H),2.49 (m, 1H).

EXAMPLE 60(3)4-(thiazol-2-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

NMR (CDCl₃): δ 8.24 (br, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.42 (d, J=3.3 Hz,1H), 5.15 (m, 1H), 4.20 (dd, J=11.1, 3.0 Hz, 1H), 3.36-3.20 (m, 2H),3.03-2.83 (m, 2H), 2.41 (m, 1H).

EXAMPLE 60(4)4-(pyridin-3-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.32 (methylene chloride:methanol=10:1);

NMR (CDCl₃): δ 8.70 (dd, J=4.8, 1.8 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H),8.13 (br, 1H), 7.71 (dt, J=8.1, 1.8 Hz, 1H), 7.39 (dd, J=8.1, 4.8 Hz,1H), 4.38 (dd, J=11.1, 2.7 Hz, 1H), 3.75 (dt, J=14.1, 2.7 Hz, 1H), 3.21(ddd, J=14.1, 12.0, 2.7 Hz, 1H), 3.11 (m, 1H), 2.98 (dd, J=14.1, 10.8Hz, 1H), 2.76 (m, 1H), 2.31 (m, 1H).

EXAMPLE 60(5)4-(1,3-dioxaindan-5-yl)-6,7,9,9a-tetrahydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.30 (chloroform:methanol=9:1);

NMR (CD₃OD): δ 8.10-8.00 (brs, 1H), 6.85-6.83 (m, 2H), 6.82-6.80 (m,1H), 6.01 (s, 2H), 4.33 (dd, J=10.8, 2.4 Hz, 1H), 3.83 (dt, J=13.5, 2.7Hz, 1H), 3.20-3.02 (m, 2H), 3.00-2.88 (m, 1H), 2.80-2.68 (m, 1H),2.32-2.22 (m, 1H).

EXAMPLE 60(6)4-(pyridin-3-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.36 (methanol:methylene chloride=1:10);

NMR (DMSO-d₆): δ 10.99 (s, 1H), 8.66 (m, 2H), 7.90 (dt, J=7.8, 2.1 Hz,1H), 7.50 (dd, J=7.8, 4.8 Hz, 1H), 6.27 (s, 1H), 3.62 (m, 2H), 3.16 (m,2H).

EXAMPLE 60(7)4-(naphthalen-2-yl)-6,7-dihydro[1,4]thiazino[4,3-d][1,2,4]triazin-1(2H)-one

TLC: Rf 0.54 (methylene chloride:methanol=10:1);

NMR (DMSO-d₆): δ 10.96 (s, 1H), 8.04-7.95 (m, 4H), 7.62-7.53 (m, 3H),6.28 (s, 1H), 3.69-3.64 (m, 2H), 3.24-3.16 (m, 2H).

EXAMPLE 61 4-(piperazin-1-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-onehydrochloride

To a suspension of 4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one (150mg; CAS Registry No. 89981-21-5; the compound described in YakugakuZassi., 82, 302-303 (1962)) in ethylene glycol (1.6 mL) was addedpiperazine (420 mg) and the mixture was stirred at 200° C. for 7 hours.After cooling to room temperature, the reaction mixture was poured in acold saturated aqueous sodium hydrogen carbonate solution and extractedwith chloroform. The extract was washed brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel (methylene chloride:methanol=20:1→10:1) togive free form of the title compound (64 mg). To a solution of theobtained free form in methanol (2.0 mL) was added 4N hydrogenchloride-ethyl acetate solution (1 mL). The mixture was stirred at roomtemperature and concentrated. The residue was recrystallized from amixed solution of methanol and ethyl acetate to give the compound of thepresent invention (21 mg) having the following physical data.

TLC: Rf 0.46 (methylene chloride:methanol:acetic acid=20:5:2);

NMR (DMSO-d₆): δ 12.31 (s, 1H), 8.98 (brs, 2H), 3.24-3.02 (m, 8H),2.58-2.30 (m, 4H), 1.78-1.50 (m, 4H).

EXAMPLE 628-(piperazin-1-yl)-2,3,4,6-tetrahydropyrido[2,3-d]pyridazin-5(1H)-one

By the same procedure as described in Example 60→Example 59 using8-chloropyrido[2,3-d]pyridazin-5(6H)-one (the compound described inChem. Pharm. Bull., 13(5), 586-593 (1965)) instead of4-chloro-5,6,7,8-tetrahydrophthalazin-1(2H)-one, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.18 (methylene chloride:methanol:acetic acid=20:5:2);

NMR (DMSO-d₆): δ 11.51 (s, 1H), 6.12 (s, 1H), 3.26-3.04 (m, 8H),3.02-2.88 (m, 3H), 2.31 (t, J=6.0 Hz, 2H), 1.71 (m, 2H).

FORMULATION EXAMPLE 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8- 5.0 gtetrahydrophthalazin-1(2H)-one carboxymethyl cellulose calcium(disintegrating agent) 0.2 g magnesium stearate (lubricating agent) 0.1g microcrystalline cellulose 4.7 g

FORMULATION EXAMPLE 2

After mixing the following components by a conventional method, theresulting solution was sterilized by a conventional method and 5 mlportions thereof were filled in amples, respectively, and freeze-driedby a conventional method to obtain 100 amples of injection containingeach 20 mg of the active ingredient.

4-(N-(2-aminoethyl)carbamoylmethyl)-5,6,7,8- 2.0 gtetrahydrophthalazin-1(2H)-one mannitol 20 g distilled water 1000 mL

1. A fused pyridazine derivative compound represented by formula (I)

wherein R¹ is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4)hydroxy, (5) halogen atom, (6) nitro, (7) NR²R³, (8) C2-8 acyl, (9) C1-8alkoxy substituted by phenyl or (10) C2-8 acyl substituted by NR²R³, R²and R³ are each independently (1) a hydrogen atom or (2) C1-8 alkyl, Xand Y are each independently (1) C, (2) CH or (3) N,

is (1) a single bond or (2) a double bond,

(1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2)partially or fully saturated 3-10 membered mono-hetero aryl containing 1to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, Ais (1) A¹, (2) A², (3) A³, (4) A⁴ or (5) A⁵, A¹ is

A² is -E¹-E²-E³-E⁴ A³ is

A⁴ is

A⁵ is

D¹ is (1) —NR⁶C(O)—, (2) —NR⁶C(S)—, (3) —NR⁶SO₂—, (4) —CH₂—NR⁶—, (5)—CH₂—O—, (6) —OC(O)—, (7) —CH₂—NR⁶C(O)—, (8) —NR⁶C(O)NR⁷—, (9)—NR⁶C(O)O—, (10) —NR⁶C(S)NR⁷—, (11) —NR⁶— or (12) —NR⁶C(═NR⁷)—, R⁶ andR⁷ are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3)phenyl or (4) C1-8 alkyl substituted by phenyl, D2 is (1) C1-8 alkylene,(2) C2-8 alkenylene, (3) Cyc2, (4) —(C1-4 alkylene)-O—(C1-4 alkylene)-,(5) —(C1-4 alkylene)-S—(C1-4 alkylene)-, (6) —(C1-4 alkylene)-NR⁸—(C1-4alkylene)-, (7)-(Cyc2)-(C1-8 alkylene)-, (8) —(C1-8 alkylene)-(Cyc2)- or(9) —(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-, R⁸ is (1) a hydrogen atom,(2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkylsubstituted by phenyl, D³ is (1) a hydrogen atom, (2) —NR⁹R¹⁰, (3) Cyc3,(4) —OR¹¹, (5) COOR¹², (6) CONR¹³R¹⁴, (7) cyano, (8) a halogen atom, (9)—C(═CR¹⁵)NR¹⁶R¹⁷ or (10) —NR¹⁸C(═NR¹⁹)NR²⁰R²¹, R⁹ and R¹³ are eachindependently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4)C2-8 alkynyl, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8alkynyloxy or (9) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, C1-8alkylthio, cyano, hydroxy or 1 to 3 halogen atom(s), R¹⁰ and R¹⁴ areeach independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8alkenyl, (4) C2-8 alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7)C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3halogen atom(s), or (9) C1-8 alkyl substituted by C1-8 alkoxy, R¹¹ andR¹² are each independently (1) a hydrogen atom or (2) C1-8 alkyl, R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently (1) a hydrogenatom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8alkyl substituted by phenyl, R⁴ is (1) a hydrogen atom, (2) C1-8 alkyl,(3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro or (7)NR²²R²³, R²² and R²³ are each independently (1) a hydrogen atom or (2)C1-8 alkyl, E¹ is C1-4 alkylene, E² is (1) —C(O)NR²⁴—, (2) —NR²⁴C(O)—,(3) —NR²⁴—, (4) —C(O)O— or (5) —S—, R²⁴ is (1) a hydrogen atom, (2) C1-8alkyl or (3) C1-8 alkyl substituted by phenyl, E³ is (1) a bond or (2)C1-8 alkylene, E⁴ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl,(4) Cyc5, (5) NR²⁵R²⁶, (6) OR²⁷, (7) SR²⁷, (8) COOR²⁷, (9) C1-8 alkylsubstituted by two of OR²⁵, (10) C1-8 alkyl substituted by 1 to 3halogen atom(s), (11) cyano or (12) C2-8 acyl, R²⁵ is (1) a hydrogenatom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or(6) C1-8 alkyl substituted by Cyc5 or OR²⁸, R²⁶ is (1) a hydrogen atom,(2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkylsubstituted by phenyl, R²⁷ is (1) a hydrogen atom, (2) C1-8 alkyl, (3)Cyc5 or (4) C1-8 alkyl substituted by Cyc5, R²⁸ is (1) a hydrogen atomor (2) C1-8 alkyl, G¹ is C1-8 alkylene, Cyc1 is (1) partially or fullysaturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fullysaturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 heteroatom(s) selected from oxygen, nitrogen and sulfur atoms, G² is (1) ahydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8 acyl,(5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to 2substituent(s) selected from Cyc6, hydroxy and C1-8 alkoxy, (7) C1-8alkoxycarbonyl substituted by Cyc6, (8) —C(O)-Cyc6, (9) nitro, (10)NR⁴¹R⁴², (11) C1-8 alkoxy or (12) C1-8 alkyl substituted by NR⁴¹R⁴², R⁴¹and R⁴² are each dependently (1) a hydrogen atom or (2) C1-8 alkyl, R⁵is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy,(5) nitro, (6) NR²⁹R³⁰, (7) C1-8 alkyl substituted by NR²⁹R³⁰, (8)NHSO₂OH, (9) amidino, (10) cyano, (11) a halogen atom, (12) Cyc8 or (13)C1-8 alkyl substituted by Cyc8, R²⁹ and R³⁰ are each independently (1) ahydrogen atom or (2) C1-8 alkyl, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8are each independently (1) partially or fully saturated C3-10 mono- orbi-carbocyclic aryl, or (2) partially or fully saturated 3-10 memberedmono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected fromoxygen, nitrogen and sulfur atoms, Cyc7 is (1) partially or fullysaturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fullysaturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 heteroatom(s) selected from oxygen, nitrogen and sulfur atoms, with provisothat Cyc7 is not benzene, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 areoptionally substituted by 1 to 3 substituent(s) selected from (1) C1-8alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5)trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8) oxo, (9)C1-8 alkyl substituted by C1-8 alkoxy or phenyl, (10) hydroxy and (11)NR²⁹R³⁰; m and n are each independently 1 or 2, wherein (i) when A is A¹or A², then

is not

(ii) when A is A⁴ and

 then R⁵ is not hydroxy or C1-8 alkoxy, (iii) when A is A⁵, then

 is not

(iv) following compounds of (1) to (13) are excepted; (1)4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one,(2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (3)4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one, (4)4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (5)4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (6)4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (7)4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (8)4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (9)7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one,(10) 4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one,(11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (12)4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, (13)4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, or apharmaceutically acceptable salt thereof.
 2. The compound represented byformula (I) according to claim 1, wherein

is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A¹,or a pharmaceutically acceptable salt thereof.
 3. The compoundrepresented by formula (I) according to claim 1, wherein

is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A²,or a pharmaceutically acceptable salt thereof.
 4. The compoundrepresented by formula (I) according to claim 1, wherein

is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A³,or a pharmaceutically acceptable salt thereof
 5. The compoundrepresented by formula (I) according to claim 1, wherein

is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A⁴or A⁵, or a pharmaceutically acceptable salt thereof.
 6. The compoundrepresented by formula (I) according to claim 1, wherein

is partially or fully saturated 3-7 membered mono-hetero aryl containing1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atomsand A is A¹, or a pharmaceutically acceptable salt thereof.
 7. Thecompound represented by formula (I) according to claim 1, wherein

is partially or fully saturated 3-7 membered mono-hetero aryl containing1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atomsand A is A², or a pharmaceutically acceptable salt thereof.
 8. Thecompound represented by formula (I) according to claim 1, wherein

is partially or fully saturated 3-7 membered mono-hetero aryl containing1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atomsand A is A³, or a pharmaceutically acceptable salt thereof.
 9. Thecompound represented by formula (I) according to claim 1, wherein

is partially or fully saturated 3-7 membered mono-hetero aryl containing1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atomsand A is A⁴ or A⁵, or a pharmaceutically acceptable salt thereof. 10.The compound represented by formula (I) according to claim 1, wherein


11. A poly(ADP-ribose)polymerase inhibitor comprising, as an activeingredient, the compound represented by formula (I) according to claim 1or a pharmaceutically acceptable salt thereof.
 12. A preventive and/ortreatment agent for ischemic diseases, inflammatory diseases,neurodegenerative diseases, glaucoma, diabetes, diabetic complication,shock, head trauma, spinal cord injury, renal failure or hyperalgesiacomprising, as an active ingredient, the compound represented by formula(I) according to claim 1 or a pharmaceutically acceptable salt thereof.13. An antiretroviral drug comprising, as an active ingredient, thecompound represented by formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 14. A sensitizer of anticancertherapy comprising, as an active ingredient, the compound represented byformula (I) according to claim 1 or a pharmaceutically acceptable saltthereof.
 15. An immunosuppressant comprising, as an active ingredient,the compound represented by formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 16. The preventive and/ortreatment agent according to claim 12, wherein the ischemic disease iscerebral infarction.
 17. The compound or the pharmaceutically acceptablesalt according to claim 1, which is described in any one of Example 1 to62.